sertraline, Zoloft
Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder.

McDougle CJ, Epperson CN, Price LH, Gelernter J.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

Obsessive compulsive disorder (OCD) is characterized by recurrent and intrusive thoughts that are distressing (obsessions) and/or repetitive behaviors or mental acts that the person feels driven to perform (compulsions). OCD has a partly genetic basis. For treatment of OCD, potent serotonin reuptake inhibitor (SRI) drugs (clomipramine (Anafranil), fluvoxamine (Luvox), fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil)), which act on the serotonin transporter protein, are uniquely efficacious. A polymorphism in the promoter region of the gene (SLC6A4) encoding this protein, was recently reported to affect protein expression and to be associated with measures of anxiety and depression and with autism (using a family-controlled transmission disequilibrium test (TDT) design). SLC6A4 therefore has strong a priori support for potentially influencing risk for OCD: the protein it encodes is a medication target; a polymorphism in the gene affects function; and that polymorphism has been shown to be associated with behavioral phenotypes. We used the TDT with a set of 34 European-American family trios, 30 unrelated and four drawn from an extended pedigree, to test for linkage disequilibrium between OCD and alleles at the SLC6A4 promoter polymorphic locus. Of 35 heterozygous parents, 24 transmitted the 'l' SLC6A4 allele and 11 transmitted the 's' allele (chi 2 TDT = 4.83; P < 0.03). Considering only the 13 SRI drug nonresponders, there were 13 heterozygous parents, of whom 10 transmitted the 'l' allele and three the 's' allele (chi 2 TDT = 3.77; P < 0.052). These data provide preliminary support for association and linkage disequilibrium between the SLC6A4 'l' allele and OCD.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9672904&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Simultaneous determination of human plasma levels of citalopram, paroxetine, sertraline, and their metabolites by gas chromatography-mass spectrometry.

Eap CB, Bouchoux G, Amey M, Cochard N, Savary L, Baumann P.

Departement Universitaire de Psychiatrie Adulte, Hopital de Cery, Prilly-Lausanne, Switzerland. Chin.Eap inst.hospvd.ch

A gas chromatography-mass spectrometry method is presented which allows the simultaneous determination of the plasma concentrations of the selective serotonin reuptake inhibitors citalopram, paroxetine, sertraline, and their pharmacologically active N-demethylated metabolites (desmethylcitalopram, didesmethylcitalopram, and desmethylsertraline) after derivatization with the reagent N-methyl-bis(trifluoroacetamide). No interferences from endogenous compounds are observed following the extraction of plasma samples from six different human subjects. The standard curves are linear over a working range of 10-500 ng/mL for citalopram, 10-300 ng/mL for desmethylcitalopram, 5-60 ng/mL for didesmethylcitalopram, 20-400 ng/mL for sertraline and desmethylsertraline, and 10-200 ng/mL for paroxetine. Recoveries measured at three concentrations range from 81 to 118% for the tertiary amines (citalopram and the internal standard methylmaprotiline), 73 to 95% for the secondary amines (desmethylcitalopram, paroxetine and sertraline), and 39 to 66% for the primary amines (didesmethylcitalopram and desmethylsertraline). Intra- and interday coefficients of variation determined at three concentrations range from 3 to 11% for citalopram and its metabolites, 4 to 15% for paroxetine, and 5 to 13% for sertraline and desmethylsertraline. The limits of quantitation of the method are 2 ng/mL for citalopram and paroxetine, 1 ng/mL for sertraline, and 0.5 ng/mL for desmethylcitalopram, didesmethylcitalopram, and desmethylsertraline. No interferences are noted from 20 other psychotropic drugs. This sensitive and specific method can be used for single-dose pharmacokinetics. It is also useful for therapeutic drug monitoring of these three drugs and could possibly be adapted for the quantitation of the two other selective serotonin reuptake inhibitors on the market, namely fluoxetine and fluvoxamine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9679303&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Drug discrimination studies of the interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents.

Marona-Lewicka D, Nichols DE.

Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, IN 47907, USA.

MMAI (5-methoxy-6-methyl-2-aminoindan) is a nonneurotoxic, highly selective neuronal serotonin (5-HT) releasing agent. MMAI and other 5-HT releasing agents produce a robust discriminative cue in drug discrimination (DD) studies. The selective serotonin reuptake inhibitors (SSRIs) sertraline and citalopram may also serve as discriminative stimuli, but acquisition of their discrimination required almost twice as much time as for MMAI. In vitro, 5-HT release by MMAI can be blocked by selective SSRIs. However, in the present DD studies, pretreatment with fluoxetine, sertraline, or citalopram 60 min before the training drugs MMAI or (+)-MBDB produced only partial inhibition of the discriminative cue. In substitution tests, sertraline and citalopram partially mimicked the training drugs, whereas only 40% substitution occurred with fluoxetine in MMAI or (+)-MBDB trained rats. In generalization tests, the tricyclic antidepressants imipramine and clomipramine partly substituted for the sertraline, citalopram, and MMAI stimuli. The increase in extracellular 5-HT produced by SSRIs leads to a subtle or feeble drug cue that is apparently difficult for an animal to recognize. This observation contrasts with the 5-HT releasing agents, which clearly produce robust cues that are easily recognized by the animals. However, mechanism(s) responsible for the discriminative stimulus effects of SSRIs and 5-HT releasing agents seem to be similar, at least in part.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9694528&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Selective serotonin reuptake inhibitor utilization patterns: consistency across research designs.

Hutchins DS, Klein EG, Signa WF, Young CH, Gregor KJ.

Outcomes Research, PCS Health Systems, Inc., Scottsdale, Arizona 85260-6719, USA.

We examined the impact of commonly applied selection criteria on the ability of patients who are initiating antidepressant therapy to reach a stable pattern, which was defined as receipt of only the initial agent at the initial dose for 90 or more consecutive days. Patients in a large US prescription database who initiated fluoxetine, paroxetine, or sertraline therapy between February and April of 1995 were categorized as with (typical design) and without (relaxed design) commonly applied selection criteria. The percentage of patients achieving a stable pattern was then determined. We found that this percentage was significantly higher with the relaxed design (typical, 28.8%; relaxed, 32.4%) and for patients initiating fluoxetine therapy (>5.5% higher than for those initiating paroxetine or sertraline therapy). The results for fluoxetine were consistent across designs, whereas comparisons between paroxetine and sertraline yielded mixed results. Therefore, the relative relationship of the stable pattern is robust across designs for fluoxetine but not for paroxetine and sertraline. Further, application of commonly applied selection criteria may make a sample less representative and reduce the measured rates of stable antidepressant use, potentially leading to underestimation of the benefits of pharmacotherapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9737838&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Selective serotonin reuptake inhibitors reduce the spontaneous activity of dopaminergic neurons in the ventral tegmental area.

Di Mascio M, Di Giovanni G, Di Matteo V, Prisco S, Esposito E.

Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti), Italy.

Electrophysiological techniques were used to study the effects of paroxetine, sertraline, and fluvoxamine on the basal activity of dopaminergic neurons in the ventral tegmental area (VTA) of rats. Acute i.v. administrations of paroxetine (20-1280 microg/kg), sertraline (20-1280 microg/kg), and fluvoxamine (20-1280 microg/ kg) caused a slight but significant reduction in the firing rate of the VTA dopaminergic cells studied. Paroxetine produced a maximal inhibitory effect of 10 +/- 11% at the cumulative dose of 160 microg/kg. Sertraline induced a dose-related inhibition of VTA dopaminergic neurons, which reached its maximum (10 +/- 7%) at the cumulative dose of 1280 microg/kg. The effect of fluvoxamine on the basal firing rate of VTA dopaminergic neurons was more pronounced as compared to that of paroxetine and sertraline, in that it produced a maximal inhibition of 17 +/- 12% at the cumulative dose of 1280 microg/kg. Acute i.v. injections of paroxetine (20-1280 microg/kg), sertraline (20-1280 microg/kg), and fluvoxamine (20-5120 microg/kg) caused a dose-dependent decrease in the basal firing rate of serotonergic neurons in the dorsal raphe nucleus (DRN). Paroxetine and sertraline stopped the spontaneous firing of serotonergic neurons at the cumulative dose of 1280 microg/kg, whereas fluvoxamine reached the same effect only at the cumulative dose of 5120 microg/kg. Pretreatment with the 5-HTA1A receptor antagonist tertatolol (1 mg/kg, i.v.) reduced the inhibitory effects of paroxetine, fluvoxamine, and sertraline on the basal activity of serotonergic neurons in the DRN. Administration of tertatolol induced a 15-fold increase in the ED50 for fluvoxamine. The antagonistic effect of tertatolol was much less evident in blocking the inhibitory action exerted by paroxetine and sertraline on the activity of serotonergic neurons. Pretreatment with tertatolol (1 mg/kg, i.v.) potentiated the inhibitory effect of fluvoxamine on the basal activity of VTA dopaminergic neurons. Tertatolol did not affect the inhibitory action exerted by paroxetine and sertraline on these neurons. It is concluded that inhibition of the basal firing rate of dopaminergic neurons in the VTA is a common characteristic of selective serotonin reuptake inhibitors (SSRIs). The effects of SSRIs on VTA dopaminergic cell activity might be relevant for their therapeutic action and may explain the origin of the reported cases of akathisia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9744293&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression.

Harkin A, Kelly JP, McNamara M, Connor TJ, Dredge K, Redmond A, Leonard BE.

Department of Pharmacology, National University of Ireland, Galway.

The limitations of antidepressant drugs to treat depression has warranted ongoing research to identify pharmacological agents and strategies which offer a faster onset of action and greater therapeutic efficacy. Noradrenaline and serotonin are widely reported to be involved in the mechanism of action of antidepressants and the recent development of selective reuptake inhibitors of these transmitters has provided the opportunity to determine the effects of targeting these transmitter systems, alone and in combination, in an antidepressant response. The present study investigated the effects of reboxetine, a new antidepressant that selectively inhibits noradrenaline reuptake, sertraline, a selective serotonin reuptake inhibitor and a combination treatment composed of the two drugs in the olfactory bulbectomized (OB) rat model of depression. Sub-acute (2 days) administration of reboxetine (2.5, 5, and 10 mg/kg, i.p.) to sham-operated and OB rats reduced the immobility time in the forced swim test. Repeated (14 days) reboxetine (10 mg/kg) treatment attenuated the OB-related behavioural hyperactivity in the 'open-field' test. Examination of the onset of the antidepressant effect in the 'open-field' test demonstrated that reboxetine (10 mg/kg), sertraline (5 mg/kg) and the combination reduced the behavioural hyperactivity after 14 days but not before this following 3, 7 or 10 days of treatment. Reduced 5-hydroxyindoleacetic acid (5-HIAA) concentrations in amygdaloid cortex of both sham and OB rats following sertraline and combination treatments are likely to be related to acute pharmacological effects on the reuptake of 5-hydroxytryptamine (5-HT). Attenuation of the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.05 mg/kg s.c.) and clonidine (0.1 mg/kg s.c.) occurred in the reboxetine and sertraline combination treated groups following both 7 and 14 days administration indicating changes to 5-HT1A receptor and alpha2-adrenoceptor sensitivity. The results indicate that changes to 8-OH-DPAT and clonidine-induced responses occur quicker with the combination treatment than with either reboxetine or sertraline treatments alone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9932714&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Major depression and its response to sertraline in primary care vs. psychiatric office practice patients. Results of an open-label trial in Argentina.

Lyketsos CG, Taragano F, Treisman GJ, Paz J.

Neuropsychiatry and Memory Group, Johns Hopkins University, Baltimore, MD, USA.

Great strides have been achieved in recent years in the detection and treatment of major depressive disorder (MDD) in primary care settings. Little is known about the types or patients with MDD seen in primary care as compared with those seen in psychiatric office practice. Few studies have compared clinical outcomes after treatment with antidepressants in these two settings. In Argentina, the authors conducted an open-label treatment study of MDD patients in primary care (n = 469) and psychiatric office practice (n = 299). The patients were compared on baseline sociodemographic and clinical variables. These same patients were treated with sertraline 50-100 mg per day for 8 weeks. At baseline, the patients in psychiatric office practice were younger, more likely to abuse alcohol, less likely to have comorbid medical disorders, and more likely to have failed a prior treatment for depression during the current episode. The two groups did not differ significantly on depression severity or in depressive symptom profile on the Hamilton Depression Rating Scale (Ham-D). After 8 weeks of treatment, mean Ham-D scores were reduced comparably in both groups, from about 25 to about 10. Rates of adverse events were 14%-29%, depending on the follow-up interval. Adherence with treatment was high in both groups (over 95%). The patients in primary care and psychiatry office practice are similar in several ways. Significant reductions in depressive symptoms are possible in both settings, in large numbers of patients, by using doses of sertraline in the 50-100 mg range.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9989124&dopt=Abstract sertraline Zoloft