Effects Of Serotonin Reuptake Inhibitors Research Articles

The effect of serotonin reuptake inhibitors on hepatic injury induced by carbon tetrachloride

The aim of the present study was to investigate the effect of several drugs acting on serotonergic neurotransmission on the development of hepatocellular injury caused by carbon tetrachloride (CCl4) in rats. Liver damage was induced in rats by administration of CCl4 (2.8 ml/kg in olive oil, orally). Sertraline, citalopram, or fluvoxamine were administered orally once daily in association with CCl4 and for 1 week thereafter. Sibutramine was administered 1 week prior to the toxic agent and for 3 days thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. In CCl4-treated rats, sertraline (10, 20 mg/kg) reduced serum alanine aminotransferase (ALT) levels by 41.8% and 53.4%, respectively, compared to controls. Serum aspartate aminotransferase (AST) levels decreased by 37.4% and 58.2%, respectively, while alkaline phosphatase (ALP) decreased by 40.5% and 59.3%, respectively. Treatment with citalopram (5, 10, 20 mg/kg) reduced serum ALT levels by 29.8%, 35.6%, and 43.8%, AST levels by 24.2%, 29.9%, and 43%, and ALP by 17.8%, 35%, and 48.9%, respectively. Fluvoxamine (5, 10, 20 mg/kg) dose-dependently reduced the elevation of ALT levels by 42.6%, 49.9%, and 51.9%, AST levels by 40.2%, 44.6%, and 61.6%, and ALP by 8.3%, 46.8%, and 52.7%, respectively. Given as a pretreatment, sibutramine (5, 10, 20 mg/kg) reduced serum ALT levels by 52.1%, 52.2%, and 57.5%, AST levels by 53.6%, 58.4%, and 59.4%, and ALP by 46.8%, 67.6%, and 72.2%, respectively. Histopathological and histochemical examinations also indicated that CCl4-induced liver injury was less severe after treatment with the test drugs than in the CCl4 control groups. It is concluded that the administration of drugs with serotonin reuptake inhibitory properties is associated with a reduction in experimental liver injury induced by CCl4.

Decreased recognition of negative affect after selective serotonin reuptake inhibition is dependent on genotype

Selective serotonin reuptake inhibitors (SSRIs) are known to influence the information processing of emotional material in depressed patients and healthy controls. The functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been shown to interact with the effectiveness of serotonin reuptake inhibitors. It is not known whether 5-HTTLPR has an influence on emotional processing in healthy controls. We report first data with long-term SSRI administration after genetic characterization of 5-HTTLPR in a randomized, double-blind, placebo-controlled, crossover design. In 30 healthy controls, 15 homozygous for the long and 15 for the short allele of 5-HTTLPR, emotionally valent images were used to elicit positive or negative emotions. We found a diminished perception of sad and fearful information under SSRI which was significant in the long allele group. These findings emphasize the importance of genetic variance in emotion processing research.

Both synthesis and reuptake are critical for replenishing the releasable serotonin pool in Drosophila

The two main sources of serotonin available for release are expected to be newly synthesized serotonin and serotonin recycled after reuptake by the serotonin transporter. However, their relative importance for maintaining release and the time course of regulation are unknown. We studied serotonin signaling in the ventral nerve cord of the larval Drosophila CNS. Fast-scan cyclic voltammetry at implanted microelectrodes was used to detect serotonin elicited by channelrhodopsin2-mediated depolarization. The effects of reuptake were probed by incubating in cocaine, which is selective for the serotonin transporter in Drosophila. p-chlorophenylalanine, an inhibitor of tryptophan hydroxylase2, was used to investigate the effects of synthesis. Stimulations were repeated at various intervals to assess the time course of recovery of the releasable pool. Reuptake is important for the rapid replenishment of the releasable pool, on the 1 min time scale. Synthesis is critical to the longer-term replenishment (10 min) of the releasable pool, especially when reuptake is also inhibited. Concurrent synthesis and reuptake inhibition decreased both serotonin tissue content measured by immunohistochemistry (by 50%) and the initial amount of evoked serotonin (by 65%). Decreases in evoked serotonin are rescued by inhibiting action potential propagation with tetrodotoxin, implicating endogenous activity in the depletion. These results show synthesis is necessary to replenish part of the releasable serotonin pool that is depleted after reuptake inhibition, suggesting that regulation of synthesis may modulate the effects of serotonin reuptake inhibitors.

Pharmacotherapy in Paediatric Obsessive-Compulsive Disorder

Pediatric obsessive-compulsive disorder (OCD) can cause substantial impairment in academic, social and family functioning. Even though cognitive-behavioural therapy (CBT) is an effective treatment, the pharmacological option has to be taken into consideration. Effectiveness of serotonin reuptake inhibitors (SRIs) has been supported by several double-blind, placebo-controlled studies. To report the response to pharmacotherapy in children and adolescents with OCD naturalistically followed up and treated with SRIs. From a consecutive series of 257 patients (174 males and 83 females; mean age 13.6+/-2.7 years) diagnosed with OCD following a clinical interview according to DSM-IV criteria, 37 children improved significantly after psychotherapy and were excluded. The remaining 220 patients were included in the study. Eighty-nine patients (40.5%) were managed with SRI monotherapy and 131 with an SRI in combination with another medication. Compared with those who needed polypharmacy, patients managed with SRI monotherapy were younger at the time of the first consultation, had less severe symptoms at baseline, and more frequently presented with co-occurring anxiety and depressive disorders, while patients receiving polypharmacy presented with higher rates of bipolar disorder, tic disorder and disruptive behaviour disorders. 135 patients (61.4%) achieved a positive clinical response and were considered responders. When differences between responders and nonresponders at the end of follow-up were considered, irrespective of the pharmacological treatment (monotherapy or polypharmacy), responders had less severe disease at baseline, were younger at the time of the first consultation, more frequently presented with the contamination/cleaning phenotype and less frequently presented with the hoarding phenotype. Treatment refractoriness was associated with higher rates of conduct disorder and bipolar disorder, and lower rates of generalized anxiety disorder and panic disorder. Forty-three children received therapy with an atypical antipsychotic as an augmenting strategy, and 25 of these children (58.1%) became responders. Responders to augmentation were less severely impaired at baseline, while different subtypes of OCD were similar between responders and nonresponders, as were patterns of co-morbidity. Our study suggests that putative variables associated with response to pharmacological treatment of paediatric OCD can be defined, and can help improve treatment strategies.

Journal Digest

Journal Digest

Reversal Learning as a Neuropsychological Indicator for the Neuropathology of Obsessive Compulsive Disorder? A Behavioral Study

Reversal Learning as a Neuropsychological Indicator for the Neuropathology of Obsessive Compulsive Disorder? A Behavioral Study

Reversal Learning as a Neuropsychological Indicator for the Neuropathology of Obsessive Compulsive Disorder? A Behavioral Study

A dysfunction of the fronto-striatal loop has been associated with obsessive-compulsive disorder (OCD). Functional imaging studies suggest that reversal learning is affected by deficits in fronto-striatal brain areas and thus should be impaired in patients with OCD. The authors compared patients with OCD and healthy comparison subjects on a reversal learning task. Correlation analyses and group comparisons showing prolonged reaction times of different response parameters are associated with increasing severity of compulsions. The reversal learning task has been shown to be associated with ventral fronto-striatal brain activation by functional magnetic resonance imaging (fMRI) in healthy comparison subjects. The purpose of this article is to suggest that the reversal learning task can be used as a neuropsychiatric measurement of the ventral fronto-striatal dysfunction in OCD.

The effect of repetitive transcranial magnetic stimulation add on serotonin reuptake inhibitors in panic disorder

Background:The Repetitive Transcranial Magnetic Stimulation (rTMS) can modulate the cortical activity. The goal of our study was to assess whether the rTMS would facilitate effect of serotonin reuptake inhibitors in patients suffering from panic disorder.Method:Fifteen patients suffering from panic disorder resistant to serotonin reuptake inhibitor (SRI) therapy were randomly assigned to either active or to sham rTMS. The aim of the study was to compare the 2 and 4 weeks efficacy of the 10 sessions 1 Hz rTMS with sham rTMS add on SRI therapy. We used 1 Hz, 30 minutes rTMS, 110% of motor threshold administered over the right dorso-lateral prefrontal cortex (DLPFC). The same time schedule was used for sham administration. Fifteen patients finished the study. The psychopathology was assessed using the rating scales CGI, HAMA, PDSS and BAI before the treatment, immediately after the experimental treatment and 2 weeks after the experimental treatment by an independent reviewer.Results:Both groups improved during the study period but the treatment effect did not differ between groups in any of the instruments.Conclusion:The low frequency Repetitive Transcranial Magnetic Stimulation administered over the right dorso-lateral prefrontal cortex after 10 sessions did not differ from sham the Repetitive Transcranial Magnetic Stimulation that was add on serotonin reuptake inhibitors in patients suffering from panic disorder.Supported by the project n. MSMT CR 1M0517

The role of 5-HT2A and 5-HT2C receptors in the signal attenuation rat model of obsessive–compulsive disorder

Serotonin 5-HT2A and 5-HT2C receptors have been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and in the mechanism mediating the anti-compulsive effects of serotonin reuptake inhibitors. Yet it is currently unclear whether activation or blockade of these receptors would have an anti-compulsive effect. The present study tested the effects of 5-HT2A and 5-HT2C activation and blockade in the signal attenuation rat model of OCD. In this model, 'compulsive' behaviour is induced by attenuating a signal indicating that a lever-press response was effective in producing food. Experiments1-4 revealed that systemic administration of the 5-HT2C antagonist RS 102221 (2 mg/kg) selectively decreases compulsive lever-pressing, whereas systemic administration of the 5-HT2A antagonist MDL11,939(0.2-5 mg/kg) or of the 5-HT2A/2C agonist DOI (0.05-5 mg/kg) did not have a selective effect on this behaviour. Experiments 5 and 6 found that systemic co-administration of DOI (0.5 mg/kg) withMDL11,939 (1 mg/kg) or with RS 102221 (2 mg/kg) had a non-selective effect on lever-press responding,with the former manipulation increasing and the latter manipulation decreasing lever-pressing. Finally,experiment 7 demonstrated that administration of RS 102221 directly into the orbitofrontal cortex also exerts an anti-compulsive effect. The results of these experiments suggest that blockade of 5-HT2Creceptors may have an anti-compulsive effect in OCD patients, and that this effect may be mediated by5-HT2C receptors within the orbitofrontal cortex.

Fish on prozac: Effect of serotonin reuptake inhibitors on cognition in goldfish.

The authors studied the effect of fluoxetine (a specific serotonin reuptake inhibitor--SSRI) on active avoidance learning in fish. In an active, two-way, shuttle-box avoidance task we compared escape and avoidance of shock among fish receiving chronic administration of fluoxetine (Prozac), others receiving a 5-HT(1A) receptor antagonist (WAY 100,635; Sigma, St. Louis, MO) and controls. The receptor-blocked group performed significantly more Avoids than the fluoxetine group, which was lowest in performance, or than controls, which were slightly higher, and not significantly different from, the fluoxetine group. This conforms to results reported in rats. Active avoidance learning may be stimulated by the 5-HT(1A) receptor antagonist. Fluoxetine-treated fish seemed less active in their home tanks than controls or blocker-treated fish. These results suggest that at the dosages used in this experiment, the 5-HT(1A) receptor antagonist WAY 100,635 may have positive effects on cognition in fishes and its action may not necessarily be restricted to blockage of 5 HT reuptake inhibition. It seems that serotonin mechanisms may be highly conserved in vertebrate evolution.

"Fish on prozac: Effect of serotonin reuptake inhibitors on cognition in goldfish": Correction.

"Fish on prozac: Effect of serotonin reuptake inhibitors on cognition in goldfish": Correction.

Antidepressants for the Treatment of Chronic Pain

Chronic pain represents one of the most important public health problems and, in addition to classical analgesics, antidepressants are an essential part of the therapeutic strategy. This article reviews available evidence on the efficacy and safety of antidepressants in major chronic pain conditions; namely, neuropathic pain, headaches, low back pain, fibromyalgia, irritable bowel syndrome (IBS) and cancer pain. Studies, reviews and meta-analyses published from 1991 to March 2008 were retrieved through MEDLINE, PsycINFO and the Cochrane database using numerous key words for pain and antidepressants. In summary, evidence supports the use of tricyclic antidepressants in neuropathic pain, headaches, low back pain, fibromyalgia and IBS. The efficacy of the newer serotonin and norepinephrine reuptake inhibitors is less supported by evidence, but can be recommended in neuropathic pain, migraines and fibromyalgia. To date, evidence does not support an analgesic effect of serotonin reuptake inhibitors, but beneficial effects on well-being were reported in several chronic pain conditions. These results are discussed in the light of current insights in the neurobiology of pain, the reciprocal relationship between pain and depression, and future developments in this field of research.

Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain

The pharmacologic management of fibromyalgia is based on the emerging evidence that pain in this disorder is primarily related to central pain sensitization. There is strong evidence that tricyclic antidepressants are effective, and moderate evidence for the effectiveness of serotonin reuptake inhibitors and dual serotonin-norepinephrine reuptake inhibitors. Recent work suggests that the anti-seizure medications pregabalin and gabepentin are also effective. The only analgesic demonstrated to be helpful is tramadol.

GIRK Channels as a Target for SSRIs. Focus on “Reduced 5-HT1A- and GABAB Receptor Function in Dorsal Raphe Neurons Upon Chronic Fluoxetine Treatment of Socially Stressed Rats”

One of the most enigmatic problems in neurobiology is the apparent disconnect between rapid effects of serotonin reuptake inhibitors (SSRI) on extracellular serotonin (5-HT) levels and the slow onset of the therapeutic antidepressant effects of these drugs. Indeed, SSRIs increase extracellular 5-HT

Enhanced reactivity of 5-HT1A receptors in the rat dorsal periaqueductal gray matter after chronic treatment with fluoxetine and sertraline: Evidence from the elevated T-maze

Behavioral evidence indicates that sensitization of 5-HT1A and 5-HT2A receptors in the dorsal periaqueductal gray (DPAG) may underlie the therapeutic effect of serotonin reuptake inhibitors (SRIs) in panic disorder. These results were obtained from studies using animal models that associate escape behavior with panic attacks, such as the elevated T-maze. In this test, chronic administration of the non-selective SRI imipramine enhances the inhibitory effect on escape caused by the intra-DPAG injection of the 5-HT1A receptor agonist 8-OH-DPAT. We here evaluated the generality of this finding by investigating the effect of chronic administration of two selective SRIs (SSRIs), fluoxetine and sertraline, on the reactivity of the rat DPAG 5-HT1A receptors. The results showed that both SSRIs inhibited escape behavior in the elevated T-maze, suggestive of a panicolytic-like effect. Whereas intra-DPAG injection of a low dose of 8-OH-DPAT (0.4 nmol) had no effect on escape in control animals, it significantly enhanced the inhibitory effect caused by the SSRIs on this response. Microinjection of 8-OH-DPAT in SSRI-treated rats also inhibited the acquisition of inhibitory avoidance, another defensive response measured by the elevated T-maze. The results indicate that chronic administration of fluoxetine and sertraline sensitizes 5-HT1A receptors in the DPAG. Overall, they support the view that facilitation of 5-HT1A receptor-mediated neurotransmission in the DPAG is implicated in the therapeutic effect of SRIs on panic disorder.

How should we inform patients about antidepressants? A study comparing verbal and written information

Objective. To compare the efficacy of verbal, written and, combined verbal and written information about selective serotonin reuptake inhibitors in patients with depression. Method. Patients with a diagnosis of major depression who were prescribed selective serotonin reuptake inhibitors (n=104) were randomly allocated to verbal (n=34, 18F 16M), written (n=38, 19F 19 M) and verbal and written information (n=32, 18F 14M) groups, the content of the verbal and written information being exactly the same. Beck depression inventory was used to evaluate the depressive symptoms. Patients were called back after 10–14 days and their retention of the knowledge was measured. Results. The total retention scores of the verbal group, written group and the combined written and verbal group were 12.85±2.19, 7.39±2.85, and 13.19±2.12, respectively. The total scores of the verbal and the combined verbal and written information groups were significantly higher than those of the written group. The information scores had a significant positive correlation with education level. Conclusion. The retention of verbal information given to patients with low levels of depression concerning the effects and side effects of serotonin reuptake inhibitors is higher than written information. Further studies with more severely depressed patients, comparing the basal information level and the information level after the intervention and the effect of information on compliance are needed.

Raynaud-Phänomen in der Dermatologie

While primary Raynaud phenomenon (RP) only rarely leads to complications, secondary RP when associated with systemic sclerosis (SSc) frequently results in necrosis, ulcers or even gangrene. Therefore timely therapeutic intervention is required. Management of RP includes physical therapy, avoidance of triggers, and a variety of medications, depending on the disease severity. On the basis of published studies and of our own experience we suggest: a) for primary and uncomplicated secondary RP, calcium channel blockers in adequate doses; b) for SSc-associated secondary RP with hypertension, cardial or renal involvement, drugs which interfere with angiotensin; c) in case of concomitant depression, exploitation of the vasodilatory effects of serotonin reuptake inhibitors, d) in presence of ulcers or marked trophic alterations, intravenous administration of iloprost, e) for recalcitrant cases and endangered digits, sildenafil, f) for prevention of severe relapses, the endothelin-receptor antagonist bosentan. The drugs mentioned in c-f are not approved for RP and used off-label. In patients with secondary SSc-associated RP, timely therapy can reduce the percentage of complications such as ulcers or amputations. In addition, timely treatment of RP possibly retards ensuing fibrotic processes.

O-31: Antidepressant-associated changes in semen parameters

ObjectiveTo identify a relationship between antidepressant medication use and impaired semen parameters in a subset of male infertility patients.DesignCase report.Materials and methodsWe have identified two patients who have had severely impaired sperm concentration and motility closely associated with the use of antidepressant medications. We describe the temporal association between abnormal semen parameters and antidepressant therapy in these two patients (who had normal semen parameters off of any medication) and were identified during evaluation for male infertility.ResultsView Large Image Figure ViewerDownload (PPT)ConclusionMedications used for the treatment of depression may have a negative, reversible effect on male fertility. Serotonin-reuptake inhibitor antidepressants may affect sperm transport, resulting in impaired sperm motility and concentration for some patients. Further controlled studies of the effect of serotonin reuptake inhibitors on semen parameters are warranted to identify the clinically significant frequency of this effect. ObjectiveTo identify a relationship between antidepressant medication use and impaired semen parameters in a subset of male infertility patients. To identify a relationship between antidepressant medication use and impaired semen parameters in a subset of male infertility patients. DesignCase report. Case report. Materials and methodsWe have identified two patients who have had severely impaired sperm concentration and motility closely associated with the use of antidepressant medications. We describe the temporal association between abnormal semen parameters and antidepressant therapy in these two patients (who had normal semen parameters off of any medication) and were identified during evaluation for male infertility. We have identified two patients who have had severely impaired sperm concentration and motility closely associated with the use of antidepressant medications. We describe the temporal association between abnormal semen parameters and antidepressant therapy in these two patients (who had normal semen parameters off of any medication) and were identified during evaluation for male infertility. Results ConclusionMedications used for the treatment of depression may have a negative, reversible effect on male fertility. Serotonin-reuptake inhibitor antidepressants may affect sperm transport, resulting in impaired sperm motility and concentration for some patients. Further controlled studies of the effect of serotonin reuptake inhibitors on semen parameters are warranted to identify the clinically significant frequency of this effect. Medications used for the treatment of depression may have a negative, reversible effect on male fertility. Serotonin-reuptake inhibitor antidepressants may affect sperm transport, resulting in impaired sperm motility and concentration for some patients. Further controlled studies of the effect of serotonin reuptake inhibitors on semen parameters are warranted to identify the clinically significant frequency of this effect.

The effects of serotonin reuptake inhibitors on locomotor activity in gerbils

In the current study we examined the effects of serotonin reuptake inhibitors on the locomotor activity of gerbils, and undertook experiments to understand the mechanisms involved in their effects. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine (1–30 mg/kg, i.p.) and escitalopram (0.03–10 mg/kg, i.p.) dose-dependently increased locomotor activity, whereas the serotonin and noradrenaline reuptake inhibitor duloxetine (0.3–30 mg/kg, i.p.) did not. The noradrenaline reuptake inhibitor (NRI) reboxetine, which alone did not significantly affect locomotion (1–30 mg/kg, i.p.), markedly reduced the effects of escitalopram. The locomotor effects of fluoxetine and escitalopram were dependent on novelty since both compounds showed rapid habituation in novel cages and were inactive when tested in home cages. Both diazepam (0.3–10 mg/kg, i.p.) and d-amphetamine (0.3–10 mg/kg, s.c.) increased locomotor activity but only the effects of diazepam were novelty-dependent. The finding that SSRIs increased locomotion, with a negative modulatory role for NRI, in a novelty-dependent manner, similar to diazepam, suggests that anxiety plays an important role in the present paradigm. The increase in locomotion as observed in our test conditions can be readily used as a selective and sensitive in vivo assay for serotonin transport inhibition in gerbils.

Augmentation Strategies to Improve Treatment of Major Depression

The monoamine hypothesis has dominated almost forty years the psychopathology of depression. Yet this has not lead to antidepressants that are significantly more efficacious than the early tri- and tetracyclics from which they have evolved. Alternative hypotheses such as those involving adult neurogenesis or components of the hypothalamic-pituitaryadrenal- axis are either too premature or have not lead to drugs with improved antidepressant activity. Antidepressants may not be perfect, both in terms of efficacy and side effects, however their performance may be improved by making use of so-called augmentation strategies. Augmentation strategies that have potential to hasten and/or improve the therapeutic effect of antidepressants, in particular serotonin reuptake inhibitors, can have different forms. They can be aimed at reducing comorbid symptoms, such as anxiety, or they may be directed to processes that counteract the effect of serotonin reuptake inhibitors. Examples of the latter are those involving 5-HT1A and 5-HT1B autoreceptors, 5-HT 2C receptors and the availability of tryptophan. Another option could be exploring neuropeptide/serotonin interactions. The various augmentation strategies are reviewed in the context of literature data regarding neurobiology and pharmacotherapy of major depression.