Paroxetine. A review of its pharmacology, therapeutic use in depression and therapeutic potential in diabetic neuropathy

Paroxetine is a selective serotonin reuptake inhibitor effective in a once-daily administration regimen in the treatment of depression. In elderly patients (aged > or = 60 years) with major depression, short term (6 weeks) treatment with paroxetine produces clinical improvements significantly superior to those seen with placebo and similar to those with tricyclic antidepressant agents, mianserin and fluoxetine. There is evidence that paroxetine has positive effects on co-existing anxiety and does not precipitate agitation. Paroxetine has also shown potential in the symptomatic treatment of diabetic neuropathy; however, further clinical experience is needed to confirm this preliminary result. Short term paroxetine therapy is associated with fewer anticholinergic and CNS adverse effects, but generally more gastrointestinal disturbances, than tricyclic antidepressants and mianserin. Unlike the tricyclic agents, paroxetine does not significantly affect cardiovascular function or impair psychomotor performance. This tolerability profile should be particularly beneficial in elderly patients, who are generally more susceptible than younger patients to the anticholinergic and CNS adverse events associated with tricyclic antidepressant drugs, and in whom there is a higher prevalence of pre-existing cardiovascular disease. It also suggests an important potential advantage over tricyclic antidepressants in the setting of overdosage. Thus, primarily because of its better tolerability profile and potentially lower toxicity in overdosage and in patients with cardiovascular disease, paroxetine appears to be a more attractive option than tricyclic antidepressants for the treatment of depression in late life. Future research should attempt to define more fully the efficacy of paroxetine as long term prophylactic therapy for recurrent depression and to assess how its overall therapeutic profile compares with other selective serotonin reuptake inhibitors in the elderly.     

Fluoxetine tenth anniversary update: the progress continues

This tenth anniversary review/update of fluoxetine concentrates on the past 5 years of its clinical application. The mechanism of action of fluoxetine; its metabolism; its efficacy in patients with various diagnostic subgroups of depression, patients with coincident medical disease, children and adolescents with depression, patients with eating disorders, and patients with obsessive-compulsive disorder (OCD); its long-term (maintenance) efficacy; its side effects and toxicity; and pharmacoeconomic considerations are reviewed. Pharmacotherapy is currently the only proven method for treating major depressive disorder that is applicable to all levels of severity of major depressive illness. Since its introduction 10 years ago, fluoxetine has been available to psychiatrists, primary care physicians, and other nonpsychiatric physicians as full-dose effective pharmacotherapy for patients with depression. Fluoxetine has been widely prescribed by physicians knowledgeable in pharmacology and in the treatment of depression because of its proven efficacy (ie, equal to that of tricyclic antidepressants [TCAs]), its ease of administration (with full therapeutic dosing usually starting from day 1), its generally benign side-effect profile, its remarkable safety in over-dose, and its proven effectiveness in the most common depressed patient population--anxious, agitated, depressed patients--as well as in patients with various subtypes and severities of depression. In more recent years it has also proved effective in the treatment of bulimia, an entity for which only limited or inadequate treatment options had been previously available. In OCD, fluoxetine, with its more acceptable side-effect profile and greater ease of dosing, presents a favorable alternative to previous drug therapy and is useful in treating both obsessions and compulsions. Fluoxetine is currently recognized among clinicians as efficacious in treating anxiety disorders and is being used successfully in special depressed populations such as patients with medical comorbidity, elderly patients, adolescents, and children. Rapid discontinuation or missed doses of short-half-life selective serotonin reuptake inhibitors, TCAs, and heterocyclic antidepressants are associated with withdrawal symptoms of a somatic and psychological nature, which cannot only be disruptive, but can also be suggestive of relapse or recurrence of depression. In striking contrast to these short-half-life antidepressants, fluoxetine is rarely associated with such sequelae on sudden discontinuation or missed doses. This preventive effect against withdrawal symptoms on discontinuation of fluoxetine is attributed to the unique extended half-life of this antidepressant. Current studies show that the overall increased effectiveness of fluoxetine in treating depression compensates for its higher cost, compared with older drugs, by reducing the need for physician contact because of increased compliance and less need of titration, and by reducing premature patient discontinuation, thereby yielding fewer relapses, less recurrence, and less reutilization of mental health services.     

Pathology of MEN-1: morphology, clinicopathologic correlations and tumour development

Augmentation therapy is used for those situations where a patient's depression is either treatment-resistant, or partially and/or insufficiently responsive to treatment. It also may be used to attempt to induce a more rapid treatment response. Using drugs together may increase the risk of adverse effects, through potentiation of existing adverse effects or alterations in plasma concentrations of the drug. It is important that clinicians are aware of potential risks of augmentation therapy. Lithium augmentation of a tricyclic antidepressant is relatively well tolerated and the dangers are no greater than using these medications on their own. There are also no reports of serious adverse events when lithium is added to a monoamine oxidase inhibitor. With lithium augmentation of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) therapy there have been case reports of the development of a central serotonin syndrome, and thus caution must exercised. A serious concern when using a tricyclic antidepressant to augment an SSRI is the effect of the SSRI on the cytochrome P450 system and the resulting significant increase in tricyclic antidepressant blood concentrations. Augmentation with thyroid hormones appears to be well tolerated and effective. Case reports and open studies indicate that augmentation with buspirone and the psychostimulants, carbamazepine and valproic acid (valproate sodium) is effective and results in minimal adverse effects. However, there is no empirical evidence supporting these results. Recent work supports the tolerability and efficacy of pindolol augmentation. Considerable caution should be exercised when combining psychotropic drugs. The practitioner should only do so with a full knowledge of the compounds involved and their pharmacological properties.     

A fatal drug interaction between clozapine and fluoxetine

A case is presented of a fatal drug interaction caused by ingestion of clozapine (Clozaril) and fluoxetine (Prozac). Clozapine is a tricyclic dibenzodiazepine derivative used as an "atypical antipsychotic" in the treatment of severe paranoid schizophrenia. Fluoxetine is a selective serotonin reuptake inhibitor used for the treatment of major depression. Clinical studies have proven that concomitant administration of fluoxetine and clozapine produces increased plasma concentrations of clozapine and enhances clozapine's pharmacological effects due to suspected inhibition of clozapine metabolism by fluoxetine. Blood, gastric, and urine specimens were analyzed for fluoxetine by gas chromatography/mass spectrometry (GC/MS) and for clozapine by gas-liquid chromatography (GLC). Clozapine concentrations were: plasma, 4.9 micrograms/mL; gastric contents, 265 mg; and urine, 51.5 micrograms/mL. Fluoxetine concentrations were: blood, 0.7 microgram/mL; gastric contents, 3.7 mg; and urine 1.6 micrograms/mL. Norfluoxetine concentrations were: blood, 0.6 microgram/mL, and none detected in the gastric contents or urine. Analysis of the biological specimens for other drugs revealed the presence of ethanol (blood, 35 mg/dL; vitreous, 56 mg/dL; and urine 153 mg/dL) and caffeine (present in all specimens). The combination of these drugs produced lethal concentrations of clozapine and high therapeutic to toxic concentrations of fluoxetine. The deceased had pulmonary edema, visceral vascular congestion, paralytic ileus, gastroenteritis and eosinophilia. These conditions are associated with clozapine toxicity. The combined central nervous system, respiratory and cardiovascular depression of these drugs was sufficient to cause death. The death was determined to be a clozapine overdose due to a fatal drug interaction.     

Differential effects of chronic antidepressant treatment on swim stress- and fluoxetine-induced secretion of corticosterone and progesterone

Hypersecretion of cortisol occurs in numerous patients with major depression and normalizes with clinical recovery during the course of chronic antidepressant treatment. These clinical data suggest that investigation of the effects of antidepressant treatments on the regulation of the brain-pituitary-adrenal axis may assist in elucidating the therapeutic basis of antidepressant actions. In the present investigation, both swim stress and acute fluoxetine challenge increased release of corticosterone and progesterone to reflect an activation of the brain pituitary-adrenal axis. The effects of chronic antidepressant treatment (21 days) on corticosterone and progesterone secretion induced by these challenges were investigated. Chronic fluoxetine treatment (5 mg/kg/day) completely blocked the increased secretion of corticosterone and progesterone in response to the acute fluoxetine challenge. Chronic treatment with desipramine, imipramine or amytriptyline (15 mg/kg/day) also markedly attenuated fluoxetine-induced corticosterone and progesterone secretion. However, chronic treatment with the monoamine oxidase inhibitors, phenelzine (5 mg/kg) and tranylcypromine (5 mg/kg), did not affect this hormonal response to acute fluoxetine challenge. Plasma levels of fluoxetine after acute challenge were not significantly different for the various chronic antidepressant treatment conditions from the chronic saline controls; therefore, an increase in the metabolism of fluoxetine can not explain the antagonism of the fluoxetine-induced hormonal response after chronic antidepressant treatment. In contrast to the effects of selected antidepressants on acute fluoxetine-induced steroid release, chronic treatment with imipramine (20 mg/kg/day), fluoxetine (5 mg/kg/day) or phenelzine (5 mg/kg) did not significantly alter this swim stress-induced corticosterone or progesterone secretion. Because chronic fluoxetine and tricyclic antidepressant drugs blocked the acute action of fluoxetine to increase adrenal cortical secretion, but did not alter swim stress-induced secretion of these steroids, we propose that distinct neurochemical mechanisms control fluoxetine and swim stress-induced steroid release. We speculate that the substantial adaptive response to those chronic antidepressant treatments, which minimize the effect of acute fluoxetine challenge to increase in corticosterone and progesterone secretion, may be relevant to the therapeutic actions of these drugs.     

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)     

GD1alpha-replica peptides functionally mimic GD1alpha, an adhesion molecule of metastatic tumor cells, and suppress the tumor metastasis

Fluoxetine, a novel selective serotonin reuptake inhibitor utilized in the treatment of depression, is avidly bound to serum albumin and alpha-1-acid glycoprotein (AAG). AAG is an acute phase protein, and its serum levels are elevated in a variety of pathophysiological conditions including inflammation, depression, cancer, and acquired autoimmune deficiency syndrome. Further, the pharmacokinetic disposition and pharmacological activity of several highly bound drugs have been reported to be significantly altered as a result of elevated serum AAG. We investigated the effects of elevated serum AAG levels on the pharmacokinetic disposition, antidepressant activity, and steady state profile of fluoxetine and its demethylated metabolite, norfluoxetine. This was approached utilizing a novel strain of transgenic mice that expressed genetically elevated serum AAG levels severalfold over those of control mice. Serum and brain drug concentrations were determined by HPLC after fluoxetine administration. In transgenic mice, the volume of distribution and the terminal elimination half-life of fluoxetine were significantly reduced. Further, significant reductions in brain-to-serum fluoxetine concentration ratios and antidepressant activity were observed in transgenic mice, despite having higher serum drug levels than control mice. This trend in the serum continued at steady state, and brain fluoxetine levels were significantly lower in transgenic mice. The results of this study provide valuable insights regarding the consequences of elevated serum AAG levels, often seen in several disease states, on the pharmacokinetic disposition of fluoxetine.     

Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression.

The forced swimming test (FST) is a widely used behavioral screen in rodents that is both sensitive and selective for clinically effective antidepressant drugs. However, antidepressant drugs produce changes in the FST within 24 hr of treatment, in contrast to weeks required for the recovery from clinical depression, and high doses seem to be required to produce effects in most animal tests. This study examined behavioral effects in the FST after subacute and chronic treatment with low doses (1-5 mg/kg) of antidepressant drugs to determine whether chronic treatment produced behavioral effects at doses that were ineffective after subacute treatment. The antidepressants studied were desipramine, a selective norepinephrine uptake inhibitor, and fluoxetine, a selective serotonin uptake inhibitor. The results indicated that low doses of desipramine and fluoxetine produced different behavioral patterns in the FST, but only after chronic administration. The results strengthen the validity of the FST as a behavioral screen for antidepressant drugs with features similar to an animal model of depression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The forced swimming test as a model for core and component behavioral effects of antidepressant drugs

The existence of a number of classes of antidepressant drugs with diverse pharmacological effects would lead one to expect that antidepressant drugs acting through different pharmacological mechanisms should produce different behavioral effects. Animal behavioral tests used to screen antidepressant drugs do not, however, discriminate between drugs that selectively enhance serotonin or norepinephrine transmission. Several components of human depression are differently affected by drugs selectively interacting with either serotonin or norepinephrine transmission. The ideal animal model for detecting antidepressant drug effects should thus be sensitive to all antidepressant drugs and should also display multiple components that are sensitive to specific drug classes. The revised scoring of the forced swimming test corresponds to a behavioral test for antidepressant drugs that meet these criteria.     

Milnacipran. A review of its use in depression

Milnacipran is a cyclopropane derivative which acts by inhibiting noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake at presynaptic sites; no postsynaptic receptor activity has been demonstrated. It is most commonly administered at a dosage of 50 mg twice daily for the treatment of major depressive disorder. Improvement usually occurs within 2 weeks of treatment initiation, but some patients do respond sooner. Most studies which evaluated milnacipran were of short (4 to 8 weeks) duration and results were not published in full with rigorous peer review. Nonetheless, the drug is significantly more effective than placebo for the treatment of in- or outpatients with moderate to severe major depressive disorder. Limited data suggest that it may prevent relapse and be effective for long term use, although this requires confirmation. Milnacipran 200 mg/day is generally not significantly different from amitriptyline 150 mg/day in terms of onset and efficacy. However, when doses are titrated (not a requirement for milnacipran), milnacipran 50 or 100 mg/day has a slower onset than the tricyclic antidepressant. At a dosage of 100 mg/day for 4 to 12 weeks, milnacipran generally has similar efficacy to imipramine and clomipramine 150 mg/day, although milnacipran 50 to 150 mg/day had a faster onset of activity than imipramine 50 to 150 mg/day in Japanese patients. In a 6-month trial, milnacipran was less effective than clomipramine. Milnacipran 50 or 100 mg twice daily was as effective as fluoxetine 20 mg once daily or fluvoxamine 100 mg twice daily in 4- to 12-week studies. At a dosage of 50 then 100 mg daily it was also as effective as mianserin 30 then 60 mg daily in a 4-week study. However, when administered once daily (in the evening), milnacipran 100 mg/day was not as effective as fluoxetine 20 mg/day after 6 weeks. The drug is generally well tolerated, producing no more adverse events (including anticholinergic events) than placebo, selective serotonin reuptake inhibitors or mianserin and fewer adverse events than tricyclic antidepressants in clinical trials. However, dysuria has been reported in 7% of male patients receiving milnacipran. CONCLUSIONS: Data from predominantly short term trials suggest that milnacipran generally has similar efficacy to tricyclic antidepressants and SSRIs. Although further published data are required to confirm its efficacy, good tolerability profile and pharmacokinetic profile which suggests a low potential for drug interactions, milnacipran should be considered a promising agent for the treatment of patients with major depressive disorder.     

Blockage of muscle and neuronal nicotinic acetylcholine receptors by fluoxetine (Prozac)

Fluoxetine (Prozac), a widely used antidepressant, is said to exert its medicinal effects almost exclusively by blocking the serotonin uptake systems. The present study shows that both muscle and neuronal nicotinic acetylcholine receptors are blocked, in a noncompetitive and voltage-dependent way, by fluoxetine, which also increases the rate of desensitization of the nicotinic receptors. Because these receptors are very widely distributed in the both central and peripheral nervous systems, the blocking action of fluoxetine on nicotinic receptors may play an important role in its antidepressant and other therapeutical effects. Our findings will help to understand the mode of action of fluoxetine, and they may also help to develop more specific medicinal drugs.     

Antidepressive agents and breast feeding

Postpartum blues occurs in 50-80% of women. A few percent of the cases are classified as serious postpartum depression, requiring antidepressant treatment. There is a growing understanding that women should continue to breast-feed in this situation. Data concerning the transfer of antidepressants into breast milk has been researched. Calculations of the infant relative dose via breast milk were done for the drugs concerned. Few antidepressants have been studied at steady state conditions in nursing mothers. Nortriptyline and amitriptyline have minimal relative doses and can be used when breast-feeding. Doxepine should be avoided, as should lithium, which has a significant transfer. Among the serotonine-reuptake inhibitors fluoxetine has been well studied in breast milk. Since fluoxetine has a long half life and a high transfer, sertraline and possibly paroxetine are better alternatives, but the latter has not yet been studied in repeated doses. Moclobemide also lacks data from multiple dose studies, but extrapolation to steady state indicates that the relative dose is small. More observational studies should be carried out in infants breast-fed by mothers using antidepressants. In the meantime, doctors prescribing antidepressant drugs to nursing mothers should see that the infants are monitored for side effects.     

Electron microscopic immunocytological profiles in chronic fatigue syndrome

Fluoxetine is a 5-hydroxytryptamine (5-HT, serotonin)-selective reuptake inhibitor (SSRI) and is one of the main drugs used for the treatment of depression. Because it takes 2 to 3 weeks of treatment before clinical efficacy is manifest, the acute actions of fluoxetine cannot account for the clinical actions of the drug. The chronic effects of fluoxetine have not been completely delineated. The experiments detailed here investigate the chronic effects of fluoxetine on 5-HT and gamma-aminobutyric acid (GABA) receptor-mediated actions using intracellular recording techniques in hippocampal brain slices. Rats were treated with fluoxetine for 3 weeks via osmotic minipumps implanted s.c. Fluoxetine and norfluoxetine plasma levels were determined. The hippocampal pyramidal cell characteristics and the 5-HT1A and GABA(B) receptor-mediated hyperpolarization were measured in the CA1 and the CA3 subfields. The 5-HT4 receptor-mediated decrease in the slow afterhyperpolarization amplitude was also recorded in area CA1. The time constant, magnitude of the change in resistance during 300-ms hyperpolarizing current pulses and half-decay time of the sAHP were altered by chronic fluoxetine treatment in area CA1 pyramidal cells. No changes were seen in any of the active or passive membrane properties of the CA3 hippocampal pyramidal cells. Fluoxetine treatment increased the potency of 5-HT for the 5-HT1A receptor-mediated hyperpolarization in area CA1, but not area CA3, and decreased the potency of baclofen for the GABA(B) receptor-mediated hyperpolarization in area CA1, but not area CA3. The characteristics of the concentration-response curve for the 5-HT-mediated decrease in sAHP amplitude in area CA1 were not altered by fluoxetine treatment. Chronic fluoxetine selectively and differentially altered the cell characteristics and the 5-HT1A and GABA(B) receptor-mediated responses in area CA1 of the hippocampus, which forms the final common output of the hippocampus.     

Psychopharmacologic treatment of depression in the medically ill

Appropriate selection of an antidepressant agent in medically ill patients requires a careful risk-benefit assessment matching the pharmacokinetic and pharmacodynamic properties of the drug being considered against the patient's physiological vulnerabilities, potential for drug interactions, and primary symptoms of the patient's depression. While in the past antidepressant drug selection was limited by the almost sole availability of the tricyclic antidepressants, newer drugs such as selective serotonin reuptake inhibitors, bupropion, and venlafaxine have vastly simplified treating depression in the medically ill. In refractory cases of depression in patients with medical illness, electroconvulsive therapy can be used with appropriate anesthetic management.     

A meta-analysis of fluoxetine outcome in the treatment of depression

A meta-analysis was conducted on all the double-blind, placebo-controlled efficacy trials of the antidepressant fluoxetine (Prozac). This drug has become the antidepressant most frequently prescribed by psychiatrists and has been hailed by the media as a "wonder drug." Results produced a relatively modest overall effect size that was no greater than effect sizes obtained by previous meta-analyses of tricyclic antidepressants. This study also examined the possibility that bias may have contaminated study outcome ratings. Because past studies suggest that the greater frequency of side effects in active drug groups unblinds study participants, we examined the relationship between study effect sizes and the percentage of patients reporting side effects. As predicted, both clinician and patient outcome ratings correlated significantly with the percentage of patients experiencing side effects. Questions are raised about the role of side effects in mediating drug outcome results.     

Enhanced sensitivity of the MRL/MpJ mouse to the neuroplastic and behavioral effects of acute and chronic antidepressant treatments.

Adult hippocampal neurogenesis has been implicated in the pathophysiology of depression and in the therapeutic effects of antidepressant drugs. Current immunohistochemical methods that study neurogenesis are time consuming and labor intensive. Therefore, a significantly more rapid flow cytometric method was characterized to measure neurogenesis in the adult mouse brain. The sensitivity of mice to the effects of antidepressant treatments is dependent on genetic background. Thus, studies were conducted comparing the responsiveness of 2 inbred mouse strains, MRL/MpJ and C57BL/6J, to the acute and chronic effects of antidepressants on neurochemistry and behavior. Acutely, MRL/MpJ mice displayed more robust behavioral and neurochemical responses to pharmacologically distinct antidepressants than C57BL/6J mice. Chronic administration of the antidepressant drugs fluoxetine and desipramine produced robust elevations in hippocampal cell proliferation and brain-derived neurotrophic factor (BDNF) protein levels in MRL/MpJ mice. C57BL/6J mice treated similarly with antidepressant drugs were mainly unresponsive on these measures. Mice were tested in the novelty-induced hypophagia (NIH) paradigm to examine a behavioral response associated with chronic, but not acute, antidepressant treatment. Only MRL/MpJ mice were behaviorally responsive to chronic antidepressant administration in the NIH paradigm. The positive effects of chronic antidepressants on hippocampal cell proliferation and BDNF paralleled the ability of these drugs to produce changes in NIH behavior. These studies highlight the advantages of using flow cytometry to study hippocampal neurogenesis and identify the MRL/MpJ mouse as a strain with superior response to antidepressant drug treatments that may lead to a better understanding of the genetics behind antidepressant efficacy and sensitivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Epidemiology and treatment of post-stroke depression

Depression is a common and serious complication after stroke. According to epidemiological studies, at least 30% of stroke patients experience depression, both early and late after stroke. However, in clinical practice only a minority of the patients are diagnosed and even fewer are treated. There are several studies confirming the magnitude of the problem but the main conclusion which can be drawn from the few treatment studies published is that tricyclic antidepressants cannot be recommended for the treatment of post-stroke depression, mainly because of the high frequency of contraindications and adverse effects. Until now there has only been 1 double-blind, placebo-controlled treatment study from which some general conclusions can be drawn. The study evaluated a selective serotonin reuptake inhibitor (citalopram) and concluded that the drug was well tolerated and effective for the treatment of post-stroke depression. However, when treatment was initiated very early, both the treatment group and the placebo group improved equally during the first 7 weeks after stroke. This finding could indicate diagnosis difficulties during the first few weeks after stroke. A recent study, although small, comparing the combination of drugs with either noradrenergic (desipramine plus mianserin) or noradrenergic and serotonergic effects (imipramine plus mianserin) for post-stroke depression, indicated that drugs with the dual effect may be more effective. Many more double-blind placebo-controlled treatment studies and studies comparing the efficacy and adverse effects of various antidepressants in patients with post-stroke depression need to be conducted. According to 3 small studies, electroconvulsive therapy (ECT) seems to be quite well tolerated and therefore ECT may also be considered in the treatment of post-stroke depression. Future studies should also address the long term efficacy of treatment for post-stroke depression.     

Management of the depressive component of bipolar disorder

Acute bipolar depression (ABD) and breakthrough depression occurring during maintenance therapy of bipolar disorder are associated with significant morbidity and an increased risk of suicide. Lithium is an effective mood stabilizer for ABD, but its onset of antidepressant action is slow and additional antidepressant therapy is often prescribed. The extent to which other mood stabilizers (e.g., carbamazepine and valproate) have antidepressant activity is unclear. Preliminary initial research suggests three potential advantages that selective serotonin reuptake inhibitors have over tricyclic antidepressant for ABD: possibly greater efficacy, fewer adverse effects, and a lower frequency of antidepressant-induced mania. Bupropion may also have significant advantages. However, further research is needed to confirm these findings. Monoamine oxidase inhibitors are the antidepressant of choice for atypical bipolar depression. Electroconvulsive therapy (ECT) has the highest response rate of all treatments for ABD. Further research is needed to explore combination treatments with mood stabilizers and antidepressants for the effective treatment of ABD.     

Cheating in medical school: a survey of second-year students at 31 schools

This study examined mechanisms by which fluoxetine may reduce energy consumption and body weight. Women with binge-eating disorder (BED; n = 38) and age- and weight-matched women without BED (n = 32) monitored their dietary intake and concurrently recorded mood variables on a hand-held computer for 6 d of baseline and for 6 d after being randomly assigned to receive placebo or fluoxetine (60 mg). Fluoxetine reduced eating more than did the placebo on days 4-6 of treatment. The frequency of episodes was not affected, suggesting that fluoxetine affects satiety, not hunger. Fluoxetine did not preferentially reduce carbohydrate intake, did not affect snack consumption as compared with meal consumption, and did not affect negative-mood eating more than positive-mood eating, nor did fluoxetine affect subjects' mood ratings. Benefits of fluoxetine were of approximately equal magnitude for women with and without BED. However, women who reported higher energy consumption at baseline were more responsive to fluoxetine than were women who reported lower energy consumption at baseline, and binge-eating status was associated with greater energy consumption at all time points, including baseline. Fluoxetine affects dietary intake within 4 d of its consumption, and if future research shows that this remains true on repeated applications, this drug may be useful for short periods when difficulty with overeating is anticipated, such as during vacations.