sertraline, Zoloft
Chronic antidepressant treatment causes a selective reduction of mu-opioid receptor binding and functional coupling to G Proteins in the amygdala of fawn-hooded rats.

Chen F, Lawrence AJ.

Howard Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. f.chen hfi.unimelb.edu.au

We have previously documented that chronic alcohol consumption or alcohol withdrawal affects mu-opioid receptor density and receptor-mediated G protein coupling in Fawn-Hooded (FH) rat brain, especially in mesolimbic regions. FH rats demonstrate comorbid depression and high voluntary alcohol consumption; treatment with standard antidepressants improves both facets of this phenotype. Accordingly, we sought to examine whether mu-opioid receptor binding and the receptor-mediated functional coupling to G protein is affected by this drug treatment. Using quantitative autoradiography, binding of mu-opioid receptors labeled by [125I]FK33,824 (D-Ala2,N-Me-Phe4,Met(O)5-ol enkephalin) and the coupling between receptors and G proteins determined by agonist-stimulated guanosine 5'-O -(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding was mapped throughout brain sections of FH rats after 10-day treatment with vehicle, desipramine, or sertraline. Both desipramine and sertraline produced significant decreases of [125I]FK33,824 binding in many brain regions; 13 of 20 measured regions for desipramine and 16 of 20 measured regions for sertraline. The coupling efficiency of mu-opioid receptors to G proteins was determined by an increase of [35S]GTPgammaS binding induced by stimulation with the mu-opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (10 microM). In contrast to the receptor binding profile, functional coupling of receptors to G proteins was only significantly reduced in the amygdala, whereas it remained unchanged in other regions compared with control. The present findings suggest that antidepressants regulate opioid systems; however, this occurs differentially, and region-specific alteration of functional coupling of mu-opioid receptors to G proteins in the amygdala suggests that opioid function within the amygdala may be modulated by antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15121763&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Serotonin clearance in vivo is altered to a greater extent by antidepressant-induced downregulation of the serotonin transporter than by acute blockade of this transporter.

Benmansour S, Owens WA, Cecchi M, Morilak DA, Frazer A.

Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA. benmansour uthscsa.edu

Serotonin uptake, mediated by the serotonin transporter (SERT), is blocked acutely by antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), but such blockade does not correlate temporally with the onset of therapeutic improvement. Treatment with SSRIs for 21 d induced downregulation of the SERT (Benmansour et al., 1999). The time course of SERT downregulation as well as the time course for its recovery after cessation of treatment with the SSRI sertraline were investigated using tritiated cyanoimipramine to measure SERT binding sites. To determine if there was a temporal correlation between the time when sertraline induced downregulation of the SERT and when marked alteration in SERT function occurred, clearance of locally applied 5-HT into the CA3 region of hippocampus was achieved using in vivo electrochemistry. After 4 or 10 d treatment with sertraline, SERT binding sites decreased very little (15-30%), and the chronoamperometric signals for serotonin in sertraline-treated rats were comparable with ones obtained in control animals. By contrast, after 15 d of treatment, when SERT binding sites were markedly reduced by 80%, there was robust decrease in the clearance of 5-HT. Moreover, the functional consequences of SERT downregulation as measured by chronoamperometry were significantly greater than those seen after acute blockade of the SERT by SSRIs. SERT binding sites decreases are not a consequence of reduced SERT gene expression, as revealed by in situ hybridization measurements. SSRI-induced downregulation of the SERT may be a key component for the clinical response to SSRIs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12151556&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Fluoxetine and sertraline stimulate gastric acid secretion via a vagal pathway in anaesthetised rats.

Abdel Salam OM.

Department of Pharmacology, National Research Centre, Tahrir St., Dokki, Cairo, Egypt. omasalam hotmail.com

The effect of the selective serotonin reuptake inhibitors, fluoxetine and sertraline on basal, secretagogues (histamine or bethanechol)- and distention-stimulated gastric acid secretion was investigated in the urethane-anaesthetised acute gastric fistula rat. Gastric acid secretion was measured by flushing of the gastric contents with saline every 15 min. Fluoxetine (10 or 20 mg kg(-1), i.p.) produced a dose-dependent increase in basal gastric acid secretion. These stimulatory effects were abolished by vagotomy. Intraperitoneally administered sertraline also stimulated gastric acid secretion. The stimulatory effect of lower doses (5 mg kg(-1)) of sertraline was similar to that of the higher (30 mg kg(-1)) doses. The gastric secretory response to i.p. sertraline was long lasting (greater than 60 min), and blocked by vagotomy. Intraperitoneally administered fluoxetine (10 or 20 mg kg(-1)) or sertraline (5 mg kg(-1)) also increased gastric secretion induced by histamine, bethanechol or distention. The fluoxetine or sertraline stimulatory effects of histamine-induced acid secretion were abolished by vagotomy. Data indicate a stimulatory effect for fluoxetine and sertraline mediated by vagal nerve on gastric acid secretion in urethane-anaesthetised rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15225675&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Noradrenergic and serotonergic neuroendocrine responses in prepubertal, peripubertal, and postpubertal rats pretreated with desipramine and sertraline.

Carrey NJ, Dursun S, Clements R, Renton K, Waschbusch D, MacMaster FP.

Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada. Normand.Carrey iwk.nshealth.ca

OBJECTIVE: To explore whether developmental status of neurotransmitter systems may affect response to antidepressant treatment. This study investigated whether younger animals, compared with mature animals, showed the same neuroendocrine response to challenge drug probes when pretreated with a serotonergic or noradrenergic antidepressant. METHOD: Prepubertal, pubertal, and adult rats were pretreated with low- or high-dose sertraline or desipramine for 14 days. Animals were then challenged with a noradrenergic probe (clonidine for desipramine-treated animals) or a serotonergic probe (fenfluramine for sertraline-treated animals). The neurohormonal response of growth hormone to the clonidine challenge and prolactin to the fenfluramine challenge was then measured. RESULTS: In animals challenged with fenfluramine, the postpubertal control group showed a significantly higher prolactin response to fenfluramine than postpubertal animals pretreated with low- or high-dose sertraline. No differences were found in the pubertal or prepubertal group. In animals challenged with clonidine, there was a significant age by treatment interaction effect for the prepubertal group pretreated with high doses of desipramine (less growth hormone secretion) but not for the peri- or postpubertal groups. CONCLUSIONS: These data indicate neurodevelopmental factors may play a role in the functional physiology of neurotransmitter systems, which in turn may affect response to psychotropics.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12162636&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Treatment outcomes in type A and B alcohol dependence 6 months after serotonergic pharmacotherapy.

Dundon W, Lynch KG, Pettinati HM, Lipkin C.

Center for the Studies of Addiction, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6178, USA. dundon_b mail.trc.upenn.edu

BACKGROUND: Evidence supporting the use of serotonergic medications for the treatment of alcohol dependence is available from studies where pharmacotherapy targeted specific alcoholic subtypes. We previously established with Babor's alcohol typology that type A "lower risk/severity" alcoholics (n = 55) had better treatment response to 14 weeks of sertraline (200 mg/day) than placebo, and this was not found for type B "higher risk/severity" alcoholics (n = 45). The purpose of this study was to assess in this original study group whether treatment gains in the type A alcoholics were maintained or whether treatment outcomes changed for the type B alcoholics after discontinuing pharmacotherapy. METHODS: After the end of a 3-month course of 200 mg/day sertraline, the subjects were interviewed at several time points about their alcohol drinking, if any, using the timeline follow-back method. For 90% of the original study group, mixed effects and generalized estimating equation models were used to compare monthly drinking amounts over a 6-month posttreatment period with drinking amounts in the last month of treatment. RESULTS: We found that type A alcoholics who had been treated with sertraline, in contrast to placebo, maintained the good outcomes they had achieved during treatment for at least 6 months after pharmacotherapy. We found that type B alcoholics who had been treated with sertraline, in contrast to placebo, continued to show no advantage for pharmacotherapy in the 6 months after completing treatment. In addition, heavy drinking in type B alcoholics increased over the 6 months postpharmacotherapy in those initially treated with sertraline compared with placebo. CONCLUSIONS: These data support the importance of considering alcohol subtype when pharmacologically treating alcohol dependence.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15252293&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Evaluation of cognitive function of fluoxetine, sertraline and tianeptine in isolation and chronic unpredictable mild stress-induced depressive Wistar rats.

Ramanathan M, Kumar SN, Suresh B.

Neuropharmacology Laboratory, Department of Pharmacology, J.S.S. College of Pharmacy, Ootacamund 643 001, India. muthiahramanathanin yahoo.co.in

Depressive illness is generally associated with cognitive impairment. Serotonergic selective antidepressant drugs, fluoxetine (FLX), sertraline (SER) and tianeptine (TIA), are claimed to have less or no effect on cholinergic system, the key system involved in memory. In the present study, these drugs were evaluated for their influence on cognitive behavior in both depressive and non-depressive animals. Depression was induced by two models, (i) 60 days social isolation of litter; and ii) by applying chronic unpredictable mild stress for 21 days. Depression in the rats was confirmed by behavioral despair test. Transfer latency on elevated plus maze and inflexion ratio in passive avoidance step through behavior were employed to assess learning and memory. The results indicated that administration of fluoxetine; sertraline and tianeptine attenuated the cognitive deficits observed in depressive rats. In non-depressive rats these drugs produced retention deficit, which was found to be parameter and model dependent. Data suggested that, FLX and SER (SSRI's) effectively attenuated the isolation-induced depression and cognitive deficit, whereas TIA (SSRE) produced better effect in stress-induced depressive conditions. It was concluded that behavioral profiles of fluoxetine, sertraline and tianeptine on cognition were model and parameter dependent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15332495&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose.

Isbister GK, Bowe SJ, Dawson A, Whyte IM.

Discipline of Clinical Pharmacology, University of Newcastle, Newcastle Mater Misericordiae Hospital, Waratah, New South Wales, Australia. gsbite ferntree.com

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have increasingly replaced tricyclic antidepressants (TCAs) in the treatment of depression. They appear to be safer in overdose, but there is little information on their spectrum of toxicity in overdose, or relative toxicity of each agent. Objective: To determine the effect of SSRIs in overdose, as a group, and the relative toxicity of five different SSRIs. METHODS: A review of consecutive SSRI poisoning admissions to a single toxicology unit. Outcomes examined were length of stay [LOS], intensive care [ICU] admission rate, coma, seizures, electrocardiographic [ECG] abnormalities, and presence of serotonin syndrome [SS]. Logistic regression was used to model the outcome QTc >440 msec. RESULTS: There were 469 SSRI poisoning admissions analyzed after exclusions. The median LOS for all SSRI overdose admissions was 15.3 h (IQR: 10.5-21.3) and 30 of 469 (6.4%; 95% CI 4.3-9.0%) cases were admitted to ICU. The incidence of seizures was 1.9% and coma was 2.4%. Serotonin syndrome occurred in 14% of overdoses. Comparison of median QTc intervals of the five SSRIs was significantly different (p=0.0002); citalopram (450 IQR: 436-484) was individually different to fluoxetine (p=0.045), fluvoxamine (p=0.022), paroxetine (p=0.0002), and sertraline (p=0.001). The proportion of citalopram overdoses with a QTc >440 msec was 68%, differing significantly from sertraline (adjusted OR: 5.11 95% CI 2.32-11.27). Comparison of median QT intervals of the five SSRIs was statistically different (p=0.026); citalopram (400 IQR: 380-440) was individually different from sertraline (p=0.023). CONCLUSIONS: This study shows SSRIs are relatively safe in overdose despite serotonin syndrome being common. The exception was citalopram, which was significantly associated with QTc prolongation. We believe that cardiac monitoring should be considered in citalopram overdose, particularly with large ingestions and patients with associated cardiac disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15362595&dopt=Abstract sertraline Zoloft