Sociocultural influences and care of dying children in Japan and the United States

Depression is a common cause of sexual dysfunction, but also antidepressant medication is often associated with sexual side effects. This article includes two related studies. The first double-blind, placebo-controlled study was conducted in men with lifelong rapid ejaculation and aimed to assess putative differences between the major selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine, paroxetine, and sertraline) with regard to their ejaculation-delaying effect. Sixty men with an intravaginal ejaculation latency time (IELT) of 1 minute or less were randomly assigned to receive fluoxetine 20 mg/day, fluvoxamine 100 mg/day, paroxetine 20 mg/day, sertraline 50 mg/day, or placebo for 6 weeks. During the 1-month baseline and 6-week treatment periods, the men measured their IELT at home using a stopwatch. The trial was completed by 51 men. During the 6-week treatment period, the geometric mean IELT in the placebo group was constant at approximately 20 seconds. Analysis of variance revealed a between-groups difference in the evolution of IELT delay (p = 0.0004); in the paroxetine, fluoxetine, and sertraline groups there was a gradual increase to about 110 seconds, whereas in the fluvoxamine group, IELT was increased to only approximately 40 seconds. The paroxetine, fluoxetine, and sertraline groups differed significantly (p < 0.001, p < 0.001, p = 0.017, respectively) from placebo but the fluvoxamine group did not (p = 0.38). Compared with baseline, paroxetine exerted the strongest delay in ejaculation, followed by fluoxetine and sertraline. There was no clinically relevant delay in ejaculation with fluvoxamine. In men with lifelong rapid ejaculation, paroxetine delayed ejaculation most strongly, whereas fluvoxamine delayed ejaculation the least. The second double-blind, placebo-controlled study was carried out in men with lifelong rapid ejaculation (IELT < or = 1 minute) and in men with lifelong less-rapid ejaculation (IELT > 1 minute) to investigate whether data about SSRI-induced delayed ejaculation in men with rapid ejaculation may be extrapolated to men with less-rapid ejaculation. After measurement of IELT at home (using a stopwatch) during a 1-month baseline assessment, 32 men with an IELT of 1 minute or less (group 1) or more than 1 minute (group 2) were randomly assigned to receive paroxetine 20 mg/day or placebo for 6 weeks in a double-blind manner. Patients continued to measure their IELTs at home during the 6 weeks of the study. At baseline, 24 patients consistently had IELTs of one minute or less (group 1), and eight patients had IELTs of more than 1 minute (group 2). The geometric mean IELT was 14 seconds in group 1 and 83 seconds in group 2. Twelve patients in group 1 and five in group 2 were randomized to the paroxetine 20 mg/day. The percentage increase in the geometric mean IELT compared with baseline in patients treated with paroxetine was 420% (95% confidence interval [CI], 216-758%) in group 1 and 480% (95% CI, 177-1,118%) in group 2 (p = 0.81). After 6 weeks of treatment with paroxetine, the geometric mean IELT was 92 seconds in group 1 and 602 seconds in group 2 (p < 0.001). Therefore, the paroxetine-induced percentage increase in IELT seems to be independent of the baseline IELT. This suggests that ejaculation-delaying side effects of some SSRIs investigated in men with lifelong rapid ejaculation may be generalized to men with less-rapid ejaculation.     

Issues in the monopharmacotherapy and polypharmacotherapy of obsessive-compulsive disorder

Polypharmacotherapy is again becoming common place in clinical practice. Obsessive-compulsive disorder (OCD) as a single primary diagnosis is responsive exclusively to the serotonin reuptake inhibitors (SRIs) and this fact forms the major evidence supporting a central role for 5-HT (serotonin) in the pathogenesis of the disorder. Presently, the highly potent serotonin reuptake inhibitors clomipramine, fluoxetine, fluvoxamine, and paroxetine are the only agents approved by the Food and Drug Administration (FDA) for OCD, but there is evidence that other SRIs, such as sertraline, are also effective. Because OCD is often treatment refractory and highly comorbid with other psychiatric disorders, the use of polypharmacotherapy can be justified. Other serotonergic medications such as lithium, buspirone, trazodone, or fenfluramine may be useful as adjuvant treatments in treatment-refractory OCD and adjuvant antipsychotics are useful in tic disorders, personality disorders, and psychotic disorders. The usefulness of polypharmacotherapy should be tempered by adverse effects including the serotonin syndrome, withdrawal phenomena, extrapyramidal side effects, and drug-drug interactions.     

Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors

The recently introduced antidepressants, the selective serotonin reuptake inhibitors (SSRIs) [citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline], are known for their clinical efficacy, good tolerability and relative safety. They differ from each other in chemical structure, metabolism and pharmacokinetic properties. Therapeutic drug monitoring of these compounds is not widely used, as the plasma concentration ranges within which clinical response with minimal adverse effects appears to be optimal are not clearly defined. Almost all recent assays developed for the quantitative determination of SSRIs and their metabolites in blood are based either on the separation of SSRIs by high performance liquid chromatography (HPLC) or gas chromatography (GC). Citalopram and fluoxetine have been introduced as racemic compounds. There are some differences in the pharmacological profile, metabolism and pharmacokinetics between the enantiomers of the parent compounds and their demethylated metabolites. Stereoselective chromatographic methods for their analysis in blood are now available. With regard to the SSRIs presently available, no clearcut plasma concentration-clinical effectiveness relationship in patients with depression has been shown, nor any threshold which defines toxic concentrations. This may be explained by their low toxicity and use at dosages where serious adverse effects do not appear. SSRIs vary widely in their qualitative and quantitative interaction with cytochrome P450 (CYP) isozymes in the liver. CYP2D6 is inhibited by SSRIs, in order of decreasing potency paroxetine, norfluoxetine, fluoxetine, sertraline, citalopram and fluvoxamine. This may have clinical consequences with some but not all SSRIs, when they are taken with tricyclic antidepressants. Except for citalopram and paroxetine, little is known about the enzymes which control the biotransformation of the SSRIs. There have been many reports on marked pharmacokinetic interactions between fluoxetine and tricyclic antidepressants. Fluoxetine has a stronger effect on their hydroxylation than on their demethylation. Interactions observed between fluoxetine and alprazolam, midazolam and carbamazepine seem to occur on the level of CYP3A. Fluvoxamine strongly inhibits the N-demethylation of some tricyclic antidepressants of the tertiary amine type and of clozapine. This may lead to adverse effects but augmentation with fluvoxamine can also improve response in very rapid metabolisers, as it increases the bioavailability of the comedication. Fluvoxamine inhibits with decreasing potency, CYP1A2, CYP2C19, CYP2D6 and CYP1A1, but it is also an inhibitor of CYP3A. Fluoxetine and fluvoxamine have shown to increase methadone plasma concentrations in dependent patients. Some authors warn about a combination of monoamine oxidase (MAO) inhibitors with SSRIs, as this could lead to a serotonergic syndrome. Studies with healthy volunteers suggest, however, that a combination of moclobemide and SSRIs, such as fluvoxamine, should not present serious risks in promoting a serotonin syndrome. A combination of moclobemide and fluvoxamine has successfully been used in refractory depression, but more studies are needed, including plasma-concentration monitoring, before this combined treatment can be recommended. Paroxetine is a substrate of CYP2D6, but other enzyme(s) could also be involved. Its pharmacokinetics are linear in poor metabolisers of sparteine, and non-linear in extensive metabolisers. Due to its potent CYP2D6 inhibiting properties, comedication with this SSRI can lead to an increase of tricyclic antidepressants in plasma, as shown with amitriptyline and trimipramine. CYP3A has been claimed to be involved in the biotransformation of sertraline to norsertraline. Clinical investigations (with desipramine) confirmed in vitro findings that CYP2D6 inhibition by sertraline is only moderate. (ABSTRACT TRUNCATED)     

The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4'-hydroxylase activity in human liver microsomes

The inhibitory effects of four selective serotonin reuptake inhibitors (SSRIs), fluoxetine, sertraline, paroxetine and citalopram, and three metabolites (norfluoxetine, demethylcitalopram and didemethylcitalopram), on S-mephenytoin 4'-hydroxylation activities in human liver microsomes were studied. The 4'-hydroxylation of S-mephenytoin, a representative substrate toward CYP2C19, was competitively inhibited by all the SSRIs and their metabolites studied. The mean Ki values of fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylcitalopram and didemethylcitalopram were 5.2, 1.1, 2.0, 7.5, 87.3, 55.8 and 7.7 microM, respectively. The findings suggest that some SSRIs and their metabolites with a low Ki value (e.g., fluoxetine, norfluoxetine) may reduce the clearance of drugs metabolized by this isoform of P450, thereby resulting in a possible drug-drug interaction, when administered simultaneously. In addition, SSRIs and their metabolites examined herein may be substrates toward CYP2C19.     

SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients

The authors analyzed the incidence of sexual dysfunction (SD) with different selective serotonin reuptake inhibitors (SSRIs; fluoxetine, fluvoxamine, paroxetine, and sertraline) and hence the qualitative and quantitative changes in SD throughout time in a prospective and multicenter study. Outpatients (192 women and 152 men; age = 39.6 +/- 11.4 years) under treatment with SSRIs were interviewed with an SD questionnaire designed for this purpose by the authors and that included questions about the following: decreased libido, delayed orgasm or anorgasmia, delayed ejaculation, inability to ejaculate, impotence, and general sexual satisfaction. Patients with the following criteria were included: normal sexual function before SSRI intake, exclusive treatment with SSRIs or treatment associated with benzodiazepines, previous heterosexual or self-erotic current sexual practices. Excluded were patients with previous sexual dysfunction, association of SSRIs with neuroleptics, recent hormone intake, and significant medical illnesses. There was a significant increase in the incidence of SD when physicians asked the patients direct questions (58%) versus when SD was spontaneously reported (14%). There were some significant differences among different SSRIs: paroxetine provoked more delay of orgasm or ejaculation and more impotence than fluvoxamine, fluoxetine and sertraline (chi 2, p < .05). Only 24.5% of the patients had a good tolerance of their sexual dysfunction. Twelve male patients who suffered from premature ejaculation before the treatment preferred to maintain delayed ejaculation, and their sexual satisfaction, and that of their partners, clearly improved. Sexual dysfunction was positively correlated with dose. Patients experienced substantial improvement in sexual function when the dose was diminished or the drug was withdrawn. Men showed more incidence of sexual dysfunction than women, but women's sexual dysfunction was more intense than men's. In only 5.8% of patients, the dysfunction disappeared completely within 6 months, but 81.4% showed no improvement at all by the end of this period. Twelve of 15 patients experienced total improvement when the treatment was changed to moclobemide (450-600 mg/day), and 3 of 5 patients improved when treatment was changed to amineptine (200 mg/day).     

Comparison of subperiosteal vs subgaleal elevation techniques used in forehead lifts

OBJECTIVE: To describe the occurrence and management of sexual dysfunction induced by selective serotonin-reuptake inhibitors (SSRIs), to provide an overview of sexual dysfunction, reports of SSRI-induced sexual dysfunction, and management strategies. DATA SOURCES: Information was retrieved from a MEDLINE English-literature search from January 1986 to July 1998 and by review of references. Indexing terms included sexual dysfunction, antidepressants, selective serotonergic reuptake inhibitors, fluoxetine, sertraline, paroxetine, fluvoxamine, clomipramine, buspirone, nefazodone, bupropion, cyproheptadine, amantadine, yohimbine, and central nervous system stimulants. STUDY SELECTION: There are no controlled studies describing SSRI-induced sexual dysfunction or its management. Twenty-one studies are presented, including 2 open-label studies, 12 case series, and 7 case reports. SSRI-induced sexual dysfunction is described with fluoxetine, paroxetine, sertraline, and fluvoxamine for 3-24 weeks of therapy. DATA SYNTHESIS: Data were organized according to the pharmacologic agent used in the management of SSRI dysfunction, target population, SSRI implicated, type of sexual dysfunction, experimental design, and treatment response. Data were extracted from methodology and results sections of reports. Methodologic flaws included failure to account for gender differences, omission of SSRI dose and duration, and use of concomitant drugs. CONCLUSIONS: The frequency of reports suggests that SSRI-induced dysfunction is a common adverse effect; controlled studies are necessary to determine prevalence. Most reports have occurred with fluoxetine, but this phenomenon may be related to its widespread use. Further study is needed to evaluate baseline sexual function, to define target populations, and to compare SSRIs in inducing sexual dysfunction. Serotonin antagonists and dopamine agonists have been used most often to treat SSRI-induced dysfunction and have generally been effective, but controlled studies are also needed.     

Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone associated with the use of selective serotonin reuptake inhibitors: a review of spontaneous reports

OBJECTIVE: To review reported cases of hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with the use of selective serotonin reuptake inhibitors (SSRIs). DATA SOURCES: A search of MEDLINE for reports of hyponatremia and SIADH associated with the use of fluoxetine, fluvoxamine, paroxetine or sertraline published between January 1980 and May 1995. Unpublished reports of cases were requested from the pharmaceutical industry, the Ontario Medical Association, the Health Protection Branch of Health Canada, the US Food and Drug Administration and the World Health Organization. DATA SELECTION AND EXTRACTION: Spontaneous reports from postmarketing surveillance. DATA SYNTHESIS: A total of 736 cases of hyponatremia [corrected] and SIADH associated with SSRI use were reported. Fluoxetine was involved in 554 (75.3%) of the cases, paroxetine in 91 (12.4%), sertraline in 86 (11.7%) and fluvoxamine in 11 (1.5%). Reports of 30 cases were published. The remaining 706 cases were reported to monitoring bodies and the pharmaceutical industry. According to information in the published reports, the median time to onset of hyponatremia was 13 days (range 3 to 120 days). Most (83%) of the published cases involved patients 65 years of age or more, as compared with 74% of the unpublished cases. CONCLUSION: Elderly people may be at increased risk for hyponatremia associated with SSRI use. Physicians caring for elderly patients should be aware of this potentially serious but reversible adverse effect. Further research is required to determine the incidence of this adverse effect, the relative risk of hyponatremia and SIADH in different age groups and the risk associated with different SSRI drugs.     

Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine

We recently reported that fluoxetine or paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats, increase the brain content of the neurosteroid 3alpha-hydroxy-5alpha-pregnane-20-one (3alpha5alpha-ALLO) without altering the brain content of other neurosteroids. ALLO (3alpha5alpha and 3alpha5beta isomers) binds with high affinity to various gamma-aminobutyric acid (GABA) receptor A subtypes and facilitates the action of GABA at these receptors. We hypothesized that the increase of ALLO brain content induced by treatment with SSRIs could contribute to alleviating the anxiety and dysphoria associated with the symptomatology of major unipolar depression. We measured ALLO content in four cisternal-lumbar fractions of cerebrospinal fluid (CSF) before and 8-10 weeks after treatment with fluoxetine or fluvoxamine in 15 patients with unipolar major depression. The concentration of ALLO ( approximately 40 fmol/ml in each CSF fraction of three control subjects) was about 60% lower in patients with major unipolar depression. However, in the same patients, fluoxetine or fluvoxamine treatment normalized the CSF ALLO content. Moreover, a statistically significant correlation (r = 0.58; P < 0.023; n = 15) existed between symptomatology improvement (Hamilton Rating Scale for Depression scores) and the increase in CSF ALLO after fluoxetine or fluvoxamine treatment. The CSF content of PREG and PROG remained unaltered after treatment and failed to correlate with the SSRI-induced increase of CSF ALLO. The normalization of CSF ALLO content in depressed patients appears to be sufficient to mediate the anxiolytic and antidysphoric actions of fluoxetine or fluvoxamine via its positive allosteric modulation of GABA type A receptors.     

Antidepressants as first-line agents in the current pharmacotherapy of anxiety disorders.

Over the last decade, there has been a shift in the order of medications considered as first-line treatments for anxiety disorders. This transition was largely initiated by the introduction and consolidation of the selective serotonin reuptake inhibitors (SSRIs)—fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram—in the treatment of depression, and by the subsequent extension of these agents beyond depression to various anxiety disorders, such as obsessive-compulsive disorder and panic disorder. This article reviews important clinical considerations for prescribing SSRIs for the treatment of panic disorder, obsessive-compulsive disorder, social phobia, posttraumatic stress disorder, and generalized anxiety disorder. The SSRIs and newer atypical antidepressants have established equal or superior efficacy and a more favorable side effect profile when compared to their predecessors. However, the newer agents are not without side effects, such as nausea, diarrhea, insomnia, headaches, sexual dysfunction, sedation, and weight gain. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Diagnostic pearls in the management of vitreomacular disorders

Pharmacokinetic interactions of clozapine and its metabolites N-desmethylclozapine and clozapine N-oxide with the selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and paroxetine were investigated in a prospective study in schizophrenic patients under steady-state conditions. Thirty patients were treated with clozapine at a target dose of 2.5 to 3.0 mg/kg of body weight. After gradual dose escalation, serum concentrations of clozapine and two metabolites were determined twice at 7-day intervals after steady-state conditions had been reached. Then, fluvoxamine (50 mg/day) or paroxetine (20 mg/day) was added in 16 and 14 patients, respectively. Serum concentrations of clozapine and its metabolites were measured after 1, 7, and 14 days of coadministration with the SSRI. Mean trough concentrations of steady-state serum concentrations of clozapine, N-desmethylclozapine, and clozapine N-oxide were markedly elevated under fluvoxamine by about threefold of baseline concentrations whereas paroxetine induced only minor, nonsignificant changes. Estimation of the mean elimination half-life of clozapine 2 weeks after start of fluvoxamine comedication revealed an increase from 17 hours to about 50 hours whereas there was no change under paroxetine coadministration. The N-desmethylclozapine/clozapine ratio did not change significantly with either SSRI. Under monotherapy, clozapine mean serum concentrations in smokers were significantly lower by 32% compared with nonsmokers. Similarly, N-demethylation ratios were about 20 to 50% higher in smokers. Thus, in all patients, fluvoxamine induced relevant increases in serum concentrations of clozapine and its metabolites, probably by the inhibition of enzymes catalyzing the degradation of clozapine and N-desmethylclozapine, whereas paroxetine, at a usual clinically effective dosage of 20 mg/day, did not cause significant pharmacokinetic interactions.     

The cost of antidepressant overdose

Ninety percent of suicide attempts referred to a general hospital are by self-poisoning. Among women, drug overdose is the commonest means of suicide. In a retrospective naturalistic review of 200 patients who were treated in the Critical Care Unit of a general hospital following medication overdose, 12% were antidepressant overdoses. The mean duration of hospital stay for overdose with tricyclic antidepressants (TCA) was more than double that for overdose with selective serotonin reuptake inhibitors (SSRI) (7 vs 3 days; z = 2.20, p < 0.05). The dollar cost of hospital treatment for patients who overdosed on TCAs was four times greater than that for patients who overdosed on SSRIs ($22,923 vs $5,379; z = 2.30, p < 0.05). The tricyclic compounds clearly have a price advantage over more recently introduced antidepressant agents fluoxetine, sertraline, paroxetine, venlafaxine, and bupropion. The apparent cost advantage of prescribing a less expensive drug may be nullified by the cost associated with adverse consequences.     

Cardiac side-effects of two selective serotonin reuptake inhibitors in middle-aged and elderly depressed patients

Selective serotonin reuptake inhibitors (SSRIs) are the 'new' drugs of first choice for the treatment of depression in the older patient. Systematic studies on the effects of SSRIs on cardiac function are scarce, despite the high prevalence of cardiac disorders in the older depressed patient. This is a study which systematically assessed cardiac function by echocardiography in middle-aged and elderly depressed patients treated with SSRI. In a double-blind randomized trial, 20 patients were assigned to receive fluvoxamine 100 mg/day [DOSAGE ERROR CORRECTED] or fluoxetine 20 mg/day [DOSAGE ERROR CORRECTED] for 6 weeks. Cardiac function was assessed by left ventricle ejection fraction, aortic flow integral and early or passive/late or active mitral inflow, and electrocardiography. Neither SSRI significantly affected cardiac function. Compared with patients without a history of myocardial infarction and/or hypertension, patients with such a history showed a significant improvement in left ventricular ejection fraction. Despite our small study sample, these data indicate that both fluoxetine and fluvoxamine do not affect cardiac function adversely.     

Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study

CONTEXT: Although a large number of women of reproductive age use new selective serotonin reuptake inhibitors (SSRIs) and half of all pregnancies are unplanned, no data exist on the safety of these agents for the human fetus. OBJECTIVE: To assess fetal safety and risk of fluvoxamine, paroxetine, and sertraline. DESIGN: A prospective, multicenter, controlled cohort study. SETTING: Nine Teratology Information Service centers in the United States and Canada. PATIENTS: All women who were counseled during pregnancy following exposure to a new SSRI and followed up by the participating centers. Controls were randomly selected from women counseled after exposure to nonteratogenic agents. MAIN OUTCOME MEASURES: Rates of major congenital malformations. RESULTS: A total of 267 women exposed to an SSRI and 267 controls were studied. Exposure to SSRIs was not associated with either increased risk for major malformations (9/222 live births [4.1%] vs 9/235 live births [3.8%] in the controls, relative risk, 1.06, 95% confidence interval, 0.43-2.62) or higher rates of miscarriage, stillbirth, or prematurity. Mean (SD) birth weights among SSRI users (3439 [505] g) were similar to the controls (3445 [610] g) as were the gestational ages (39.4 [1.7] weeks vs 39.4 [1.9] weeks). CONCLUSION: The new SSRIs, fluvoxamine, paroxetine, and sertraline, do not appear to increase the teratogenic risk when used in their recommended doses.     

Pharmacokinetic drug interactions of new antidepressants: a review of the effects on the metabolism of other drugs

Seven of the newest antidepressants are the serotonin-selective reuptake inhibitors (fluoxetine, sertraline, paroxetine, and fluvoxamine [currently approved in the United States only for obsessive-compulsive disorder]), a serotonin-norepinephrine reuptake inhibitor (venlafaxine), a postsynaptic serotonin antagonist-presynaptic serotonin reuptake inhibitor (nefazodone), and a presynaptic-postsynaptic noradrenergic-serotonergic receptor antagonist (mirtazapine). Many of these drugs are potent inhibitors of the cytochrome P-450 enzymes (CYPs) of the liver. The isoforms of the CYPs most relevant to the use of antidepressants are CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. CYP inhibition may affect the metabolism of numerous drugs in several classes that are substrates for these isoenzymes, with potentially serious consequences. To minimize the potential for an adverse event, the practitioner must remember the drug-drug interactions, and possible consequences when one of these antidepressants is being prescribed. A "primer" on drug metabolism is included herein, which serves as a basis for understanding these interactions., Each of the isoenzymes of the CYPs is discussed in relationship to the drugs they metabolize, and appropriate cautions are recommended for concurrent administration of these new antidepressants and other drugs most frequently prescribed to elderly patients.     

Role of serotonin in obsessive-compulsive disorder

BACKGROUND: Serotonin may play a role in the pathophysiology of obsessive-compulsive disorder (OCD) because of the anti-obsessional effect of selective serotonin reuptake inhibitors (SSRIs). METHOD: The literature is reviewed on knowledge of the role of serotonergic neurons in brain function, studies on monoamine metabolites in cerebrospinal fluid (CSF), various stress neuropeptides, neuroendocrine and behavioural challenge after administration of direct and indirect serotomimetic compounds, and neuroanatomical data on brain circuits organising behaviour. RESULTS: In most of the OCD cases analysed, CSF 5-hydroxyindoleacetic acid and homovanillic acid concentrations do not significantly differ from age-corrected controls. However, a relationship appears to exist between pre-treatment levels of these metabolites and clinical response to drugs acting on the serotonin transporter. Abnormalities in CSF arginine vasopressin, corticotropin-releasing hormone, oxytocin and somatostatin levels have been reported in OCD. Long-term treatment with high-doses of clomipramine, fluvoxamine, and fluoxetine tend to correct these neuropeptide abnormalities. CONCLUSIONS: We hypothesise that continuous treatment with SSRIs alters serotonin turnover and neuropeptide expression patterns in OCD-entertaining functional forebrain/midbrain circuits.     

Discriminative stimulus properties of the serotonin uptake inhibitor sertraline.

Male rats were trained to discriminate the stimulus properties of the antidepressant serotonin (5-hydroxytryptamine [5-HT]) uptake inhibitor sertraline (10 mg/kg) from saline using the discriminated taste aversion procedure. Three other selective 5-HT uptake inhibitors, fluvoxamine (5.6 and 10.0 mg/kg), fluoxetine (10.0 mg/kg), and paroxetine (10.0 mg/kg), substituted completely for the stimulus properties of sertraline. Selective inhibitors of norepinephrine uptake, desipramine and maprotiline, also substituted for the sertraline stimulus at 18.0 mg/kg. Results show that rats can be trained to respond to sertraline as a discriminative stimulus and that sertraline generalizes to other 5-HT uptake inhibitors that are members of a class of antidepressant drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selective serotonin reuptake inhibitors dissociate fenfluramine's anorectic and neurotoxic effects: importance of dose, species and drug

Fenfluramine, a clinically prescribed appetite suppressant, has been found to damage brain serotonin (5-HT) neurons in every animal species tested to date. Recent findings indicate that fluoxetine, a selective 5-HT reuptake inhibitor (SSRI), can prevent fenfluramine-induced 5-HT neurotoxicity without blocking fenfluramine-induced appetite suppression. The purpose of our studies was several-fold: 1) To determine whether the ability for fluoxetine to dissociate fenfluramine-induced anorexia and neurotoxicity is dose-related; 2) to ascertain whether other SSRIs also prevent fenfluramine-induced neurotoxicity without altering its anorectic effect; 3) to determine whether similar fluoxetine/fenfluramine interactions are seen in another animal species (i.e., mice) and 4) to determine whether decreases in food intake seen after the fluoxetine/fenfluramine combination can be attributed to nonspecific behavioral suppression. Results from our studies indicate that fluoxetine's effects are, indeed, dose-related, because higher doses of fluoxetine are required to protect against the 5-HT neurotoxic effects of higher doses of fenfluramine. Further, our results indicate that fluoxetine's effects generalize to all other SSRIs tested (citalopram, paroxetine and sertraline), as well as to other species (mice). Finally, our results demonstrate that anorexia in animals receiving the fenfluramine/fluoxetine combination is not secondary to nonspecific behavioral suppression, because water intake is increased although food intake is decreased in the same animals. Together, these data suggest that the anorectic and 5-HT neurotoxic effects of fenfluramine may involve different mechanisms, and that by combining fenfluramine with SSRIs, it may be possible to exploit fenfluramine's clinically useful properties (e.g., anorexia) without risking brain 5-HT neural injury.     

Effects of serotonin reuptake inhibitors on hemostasis

OBJECTIVE: To examine the hematologic safety profile of the selective serotonin reuptake inhibitors (SSRIs), with particular emphasis on the effects of these drugs on platelet aggregation. METHODS: Platelet aggregation studies were undertaken at baseline, and repeated 2 and 4 weeks after the initiation of treatment with an SSRI. Other investigations undertaken included analysis of serum electrolyte and liver enzyme concentrations, complete blood count, and coagulation studies. Patients were also assessed for clinical signs of bleeding. Eight patients (7 treated with fluoxetine, 1 with paroxetine) completed the study protocol. RESULTS: Repeated ANOVA revealed no abnormalities in platelet aggregation, hematopoiesis, or coagulation profile. No patient developed clinical signs of abnormal hemostasis during the study period. A statistically significant elevation in the mean serum bilirubin concentration was detected, but this was not of clinical significance. CONCLUSIONS: Although the SSRIs may cause abnormal hemostasis, this effect is probably rare. Another possibility is that abnormal hemostasis is more likely to occur when high doses of SSRIs are administered.