Potent Serotonin Reuptake Inhibitor Research Articles

Tolerability and Efficacy of Duloxetine in a Nontrial Situation

Duloxetine, a potent serotonin and noradrenaline reuptake inhibitor, is the first drug licensed in England for use in treating stress urinary incontinence (USI). Data from double-blind placebo-controlled trials show that it is significantly more effective than placebo in lowering the frequency of incontinent episodes, but very little is known about duloxetine outside of trials sponsored by the manufacturer. This prospective observational study evaluated duloxetine in 222 women diagnosed as having either USI or mixed USI and detrusor overactivity (DOA). The results of treatment over 4 months were evaluated using the Patient Global Impression of Improvement (PGI-I) questionnaire. Two-thirds of the women received 40 mg of duloxetine twice daily from the outset, and nearly all of the rest received escalating doses up to a maximum of 40 mg twice daily. Three women received 20 mg twice daily throughout. Two thirds of women discontinued treatment because of either lack of effectiveness or adverse side effects. Withdrawal because of adverse effects was significantly more frequent in women whose initial dose was 40 mg twice daily than in those taking escalating doses. None of the side effects were considered to be serious. Safety profiles were similar for women having USI only and those with combined USI and DOA. Nine women, 7 of whom had mixed incontinence, reported that their incontinence had become worse. Four women expressed a preference for surgery rather than long-term medication despite improvement in their PGI-I scores. Considering women who did not tolerate duloxetine, the overall rate of improvement was 37%. The investigators conclude that, in a nontrial setting, women with USI or mixed USI/DOA do not tolerate duloxetine well, although an escalating dose regimen may be better received. Women with isolated USI and those with combined USI and DOA are equally likely to improve when treated with duloxetine.

Obsessive-Compulsive Disorder

OCD, a surprisingly common disorder, is often hidden by patients who have insight into the inappropriateness of their obsessional concerns and the excessive rituals they feel compelled to perform to ward off exceedingly low risk danger or more vague feelings of discomfort. Onset in childhood is common and many suffer lifelong with a few becoming incapacitated by incessant demands of their disorder. Diagnosis is straightforward once obsessions and rituals are admitted. Once recognized, treatment with cognitive behavior therapy (CBT) and potent serotonin reuptake inhibitors (SRIs) is often helpful, alone or in combination. For those with disorders unresponsive to these standard treatments, somatic treatment with multiple medications and rarely, deep brain stimulation or neurosurgical lesions may be helpful. The largest obstacle to effective treatment of OCD at present is the difficulty obtaining effective CBT which is twice as beneficial, on average, as SRIs.

A First Look at Duloxetine (Cymbalta(R)) in a Postmortem Laboratory

Duloxetine (Cymbalta) is manufactured by Eli Lilly and Company and is the newest antidepressant to be approved by the Food and Drug Administration (FDA). Duloxetine is a potent serotonin and norepinephrine reuptake inhibitor that is also used for the management of pain associated with diabetic peripheral neuropathy. With the introduction of any new drug, toxicology laboratories around the nation experience the same problems: lack of information about the chemical and physical properties of the new drug, detection methodologies from biological specimens, and interpretation of quantitative values. Since its FDA approval in 2002, the Los Angeles County Department of Coroner Toxicology Laboratory has detected and quantitated duloxetine in 12 postmortem cases. The isolation of duloxetine from postmortem specimens consisted of a basic, liquid-liquid (n-butylchloride) extraction procedure. Duloxetine was detected in our general, pharmaceutical, basic drugs screen that utilizes gas chromatography-nitrogen-phosphorus detection (GC-NPD) and GC-mass spectrometry (MS), and the quantitation was specifically by GC-MS. Linearity was achieved from 0.05 to 3.0 mg/L with the limit of detection at 0.03 mg/L. Presented are the case histories, demographics, cause/manner of death, and the postmortem tissue distribution ranges of duloxetine: central blood, not detected (ND)-0.59 mg/L (12 cases); femoral blood, ND-0.26 mg/L (9 cases); vitreous humor, ND-0.23 mg/L (4 cases); liver, 0.28-22 mg/kg (8 cases); gastric contents, 0.08-86 mg total (6 cases); bile, 0.57-3.1 mg/L (7 cases); and urine, 0.07-0.47 mg/L (6 cases). The detection and quantitation of duloxetine in these 12 case studies are considered the first to be reported in the literature; all are designed to aid the forensic toxicologist with the interpretation of his/her own casework.

Obsessive-Compulsive Disorder in Tourette Syndrome

Several lines of evidence suggest a meaningful association between obsessive-compulsive disorder and Tourette syndrome, including comorbidity, phenomenologic overlap, evidence from family and genetic studies, and the possible role of basal ganglia circuitry in both conditions. Obsessive-compulsive behaviors occur frequently in patients who have Tourette syndrome and tend to have a later onset than tics. Despite commonalities, the approaches to treating tics and obsessive-compulsive symptoms are actually quite distinct. A specialized form of cognitive behavior therapy and pharmacotherapy with a potent serotonin reuptake inhibitor are the two established first-line therapies for obsessive-compulsive disorder. An adequate trial of a serotonin reuptake inhibitor is 10 to 12 weeks in duration at doses near the upper end of the recommended range for age and weight. Cases of obsessive-compulsive disorder that do not sufficiently improve with serotonin reuptake inhibitors might benefit from adjunctive low-dose antipsychotic (eg, risperidone) medication whether or not tics are present. Warnings about an increased risk of suicidality among children and adolescents taking antidepressants for pediatric depression extend to those taking the medications for obsessive-compulsive disorder, but the risk-to-benefit ratio is more favorable in this latter population because several serotonin reuptake inhibitors have been shown to be efficacious in obsessive-compulsive disorder.

Pharmacotherapies in the Management of Obsessive—Compulsive Disorder

Few medications are effective in treating obsessive-compulsive disorder (OCD). As monotherapy, only potent serotonin (5-HT) reuptake inhibitors (SRIs) consistently exert an intrinsic therapeutic action in OCD. Their use in OCD, however, differs from their use in depression. This paper first reviews the evidence supporting the key role of 5-HT as a pivotal neurotransmitter in the anti-OCD response. Then, we describe the practicalities of SRI use, followed by the steps that can be taken when these medications do not produce an adequate clinical response. We provide specifics for the treatment of children and adolescents with OCD. We include a brief description of the brain circuitry involved in OCD and the mechanisms of action of the pharmacologic agents reported to be effective in this disorder, as well as those that are useful in depression but not in OCD. We present this information to promote better understanding of the research endeavours needed to develop new pharmacotherapeutic approaches.

An open clinical trial of venlafaxine in the treatment of pain, depressive and anxiety symptoms in fibromyalgia

Although the pathophysiology of fibromyalgia is unknown, antidepressants have proved to be successful in alleviating symptoms of fibromyalgia. The aim of this study was to evaluate the efficacy of venlafaxine in the treatment of pain in patients with fibromyalgia and the depressive and anxiety symptoms commonly seen in these patients. Twenty-one patients with fibromyalgia according to the criteria proposed by the American College of Rheumatology were included in the study. Patients were assessed for pain, depression and anxiety before and after treatment with a fixed dose of venlafaxine (75 mg/d). Second and third evaluations were carried out 5 and 10 weeks after the beginning of the therapy. There was a significant improvement in the mean intensity of pain and in depression and anxiety scores from baseline to week 5 and 10. The improvement in pain, depression and anxiety scores seemed to be independent of each other. Venlafaxine a potent inhibitor of both noradrenaline and serotonin reuptake, might be effective for both pain and comorbid depressive and anxiety symptoms independently in patients with fibromyalgia.

Mechanisms of action of current and potential pharmacotherapies of obsessive-compulsive disorder

A significant body of evidence documented that the orbitofrontal cortex (OFC) and the head of caudate nucleus are involved in the mediation of obsessive-compulsive disorder (OCD) symptoms. Potent serotonin (5-HT) reuptake inhibitors (SRIs) are the only antidepressant agents thus far shown to be effective in the treatment of OCD. The present review summarizes information on 5-HT release and the adaptive changes in pre- and postsynaptic 5-HT receptors sensitivity induced by SRI treatment in rat and guinea pig structures involved in OCD. It emphasizes that the time course for the occurrence of increased 5-HT release and terminal 5-HT 1D desensitization is congruent with the delayed therapeutic response to SRI in OCD. In addition, a greater dose of SRI inducing a greater degree of reuptake inhibition may play an essential role in this phenomenon. This is consistent with the common clinical observation that high doses of SRIs are sometimes necessary to obtain an anti-OCD effect, and with the results of some fixed-dose double blind trials showing a dose-dependent therapeutic effect of SRIs. It is hypothesized that enhanced 5-HT release in the OFC is mediated by the activation of normosensitive postsynaptic 5-HT 2-like receptors and underlies the therapeutic action of SRI in OCD. This is supported by the beneficial effect of some hallucinogens with 5-HT 2 agonistic properties in obtaining a more rapid therapeutic response. Finally, based on this knowledge, new strategies aimed at producing more rapid, effective and safe anti-OCD drugs, such as a selective action on terminal 5-HT 1D receptors, on 5-HT 2 receptors as well as on the glutamate system, are discussed.

Conformationally Restricted Homotryptamines. 2. Indole Cyclopropylmethylamines as Selective Serotonin Reuptake Inhibitors

A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for hSERT, and the preferred cyclopropane stereochemistry was determined to be (1S,2S)-trans. The cis-cyclopropanes had 20- to 30-fold less affinity than the trans, and the preferred cis stereochemistry was (1R,2S)-cis. Substitution of the indole N-1 position with methyl or ethyl groups gave a 10- to 30-fold decrease in affinity for hSERT, suggesting either a hydrogen-bonding interaction or limited steric tolerance in the region of the indole nitrogen. Compound (+)-12a demonstrated potent hSERT binding (Ki = 0.18 nM) in vitro and was more than 1000-fold less potent at hDAT, hNET, 5-HT1A, and 5-HT6. In vivo, (+)-12a produced robust, dose-dependent increases in extracellular serotonin in rat frontal cortex typical of a selective serotonin reuptake inhibitor. The maximal response produced by (+)-12a was similar to that of fluoxetine but at an approximately 10-fold lower dose.

Duloxetine hydrochloride: A new dual-acting medication for the treatment of major depressive disorder

Duloxetine hydrochloride has recently been approved by the US Food and Drug Administration for the treatment of major depressive disorder (MDD). Duloxetine is a potent inhibitor of serotonin and norepinephrine reuptake, with weak effects on dopamine reuptake. This article reviews the literature on duloxetine with regard to its pharmacodynamics, pharmacokinetics, clinical efficacy, and tolerability. A comprehensive search of MEDLINE was performed using the terms duloxetine, Cymbalta, and major depressive disorder, with no restriction on year. The Eli Lilly and Company clinical trial registry, and abstracts and posters from recent American Psychiatric Association meetings were also reviewed. Duloxetine exhibits linear, dose-dependent pharmacokinetics across the approved oral dosage range of 40 to 60 mg/d. No dose adjustment appears to be needed based on age. Duloxetine has shown efficacy in reducing depressive symptoms compared with placebo, and duloxetine recipients have shown significant improvements in global functioning compared with placebo (both, P < 0.05). Response and remission rates have been comparable to or greater than those seen with fluoxetine or paroxetine. Duloxetine is generally well tolerated, with nausea, dry mouth, and fatigue being the most common treatment-emergent adverse effects. Cardiovascular adverse effects do not appear to result in sustained blood pressure elevations, QTc-interval prolongation, or other electrocardiographic changes. Based on the available evidence, duloxetine is a well-tolerated and effective treatment for MDD in adults. Randomized head-to-head comparisons against established antidepressants are needed to determine the relative safety and efficacy of duloxetine.

Metyrapone attenuates the sequential learning deficits but not monoamine depletions following d,l-fenfluramine administration to adult rats.

Fenfluramine (FEN) is a substituted amphetamine known for its anorectic effects, without the stimulatory or abuse potential associated with other amphetamine derivatives. FEN is a potent serotonin (5-HT) releaser and reuptake inhibitor and has been shown to cause depletions of 5-HT that can last days and even weeks after administration. Administration of FEN four times on a single day also causes a prolonged increase of corticosterone (CORT) that lasts approximately 72 h following the first FEN dose. This dosing regimen also produces deficits in sequential learning as measured in the Cincinnati water maze (CWM). Adrenalectomy blocks this effect but removes more than CORT. Accordingly, the purpose of this study was to determine whether inhibiting glucocorticoid production, by administration of the 11 beta-hydroxylase inhibitor metyrapone (MET), will similarly attenuate or eliminate the sequential learning deficits seen with FEN exposure. MET (50 mg/kg) injections were administered 90 min prior to and for 3 days after FEN (four doses given at 2-h intervals). Animals pretreated with MET and treated with FEN showed no sequential learning deficits when tested 1 week following FEN administration compared to FEN alone. The depletions of monoamines were similar following FEN administration, regardless of MET treatment. Taken together, this suggests that a potential mechanism for the sequential learning deficits in FEN-treated animals is a result of prolonged increases in CORT output.

Pharmacological treatment for obsessive-compulsive disorder

The systematic investigation of obsessive-compulsive disorder (OCD) has depended on the introduction of universally accepted diagnostic criteria and comprehensive rating scales that are sensitive enough to measure small treatment-related changes, such as the Yale-Brown Obsessive Compulsive Scale (YBOCS) (Goodman et al., 1989). This contribution reviews the key clinical questions relating to pharmacotherapy for OCD (Figure 1). After 25 years of intensive pharmacological investigation, it still appears to be the case that OCD responds selectively to drugs that act as powerful inhibitors of the synaptic reuptake of serotonin – clomipramine and the selective serotonin reuptake inhibitors (SSRIs). Drugs lacking potent serotonin reuptake inhibitor (SRI) actions, such as the tricyclic antidepressants amitriptyline, nortriptyline and desipramine, and the monoamine oxidase inhibitors (MAOIs) clorgyline and phenelzine, have not been found to be effective in controlled studies. Nor is there convincing evidence supporting the efficacy of antipsychotics, benzodiazepines, lithium or electroconvulsive therapy (ECT) (Figure 2). The selectivity of the pharmacological response has generated hypotheses concerning the role of serotonin in the pathophysiology of the disorder but, so far, no unifying theory has emerged.

Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects.

Duloxetine is a potent and balanced dual inhibitor of serotonin and norepinephrine reuptake being investigated for the treatment of depression and urinary incontinence. The disposition of duloxetine was studied in four healthy human subjects after a single 20.2-mg (100.6 microCi) oral dose of [14C]duloxetine in an enteric-coated tablet. The mean total recovery of radioactivity (+/- S.E.M.) after 312 h was 90.5% (+/-0.4%) with 72.0% (+/-1.1%) excreted in the urine. Duloxetine was extensively metabolized to numerous metabolites primarily excreted into the urine in the conjugated form. The major biotransformation pathways for duloxetine involved oxidation of the naphthyl ring at either the 4-, 5-, or 6-positions followed by further oxidation, methylation, and/or conjugation. The major metabolites found in plasma were glucuronide conjugates of the following: 4-hydroxy duloxetine (M6), 6-hydroxy-5-methoxy duloxetine (M10), 4, 6-dihydroxy duloxetine (M9), and a sulfate conjugate of 5-hydroxy-6-methoxy duloxetine (M7). The major metabolites found in plasma were also found in the urine, but the urine contained many additional metabolites. In addition to duloxetine, 4-hydroxy duloxetine (M14) and an unidentified polar metabolite were observed in feces. Following [14C]duloxetine administration, Cmax was reached at a median of 6 h for both duloxetine and total radioactivity. Duloxetine accounted for less than 3% of the circulating radioactivity based on mean area under the curve values. The elimination half-life of total radioactivity (120 h) was substantially longer than that of duloxetine (10.3 h).

Enhancing action of LSD on neuronal responsiveness to serotonin in a brain structure involved in obsessive-compulsive disorder.

Potent serotonin (5-HT) reuptake inhibitors are the only drugs that consistently exert a therapeutic action in obsessive-compulsive disorder (OCD). Given that some hallucinogens were reported to exert an anti-OCD effect outlasting their psychotomimetic action, possible modifications of neuronal responsiveness to 5-HT by LSD were examined in two rat brain structures: one associated with OCD, the orbitofrontal cortex (OFC), and another linked to depression, the hippocampus. The effects of concurrent microiontophoretic application of LSD and 5-HT were examined on neuronal firing rate in the rat OFC and hippocampus under chloral hydrate anaesthesia. In order to determine whether LSD could also exert a modification of 5-HT neuronal responsiveness upon systemic administration, after a delay when hallucinosis is presumably no longer present, it was given once daily (100 microg/kg i.p.) for 4 d and the experiments were carried out 24 h after the last dose. LSD attenuated the firing activity of OFC neurons, and enhanced the inhibitory effect of 5-HT when concomitantly ejected on the same neurons. In the hippocampus, LSD also decreased firing rate by itself but decreased the inhibitory action of 5-HT. The inhibitory action of 5-HT was significantly greater in the OFC, but smaller in the hippocampus, when examined after subacute systemic administration of LSD. It is postulated that some hallucinogens could have a beneficial action in OCD by enhancing the responsiveness to 5-HT in the OFC, and not necessarily in direct relation to hallucinosis. The latter observation may have theoretical implications for the pharmacotherapy of OCD.

Determination of fluoxetine and norfluoxetine in rat plasma by HPLC with pre-column derivatization and fluorescence detection.

Both fluoxetine (FLX) and its N-demethylated metabolite, norfluoxetine (NFLX), have been reported to be potent serotonin-reuptake inhibitors. A sensitive and reliable method that allows simultaneous quantification of their plasma levels would be valuable and was developed in this work. The procedure included extraction of FLX and NFLX from plasma, fluorescence derivatization with 4-(N-chloroformylmethyl-N-methyl) amino-7-nitro-2,1,3-benzoxadiazole (NBD-COCl), separation of the derivatives on an octadecylsilica column with acetonitrile-water (55:45,v/v) as mobile phase and fluorescence detection with emission at 537 nm and excitation at 478 nm. The calibration curves were linear for FLX and NFLX concentration over the range of 10-1000 nM (r = 0.9992 and r = 0.9997) and the limits of quantitation were 10 nM in 100 micro L of plasma. Precision of intra- and inter-day RSD of less than 12% and accuracy of intra- and inter-day RE within -6.0-13% were achieved. The method described was applied to analysis of the plasma samples from rats treated with FLX hydrochloride and to the pharmacokinetic study.

Duloxetine pharmacology: profile of a dual monoamine modulator.

Dysregulation within central monoaminergic systems is believed to underlie the pathology of depression. Drugs that selectively inhibit the reuptake of central monoamines have been used clinically to alleviate symptoms of depressive illnesses. Duloxetine, a novel compound currently under investigation for the treatment of depression, binds selectively with high affinity to both norepinephrine (NE) and serotonin (5-HT) transporters and lacks affinity for monoamine receptors within the central nervous system. It has been suggested that dual inhibition of monoamine reuptake processes may offer advantages over other antidepressants currently in use. In preclinical studies, duloxetine mimics many physiologic effects of antidepressants. Consistent with other antidepressants, duloxetine, by acute administration, elevates extracellular monoamine levels, while by chronic administration it does not alter basal monoamine levels. Like the selective serotonin reuptake inhibitor, fluoxetine, by microiontophoretic application, duloxetine inhibits neuronal cell firing. However, in comparison with fluoxetine, duloxetine is a more potent serotonin reuptake inhibitor. Furthermore, in behavioral experiments, duloxetine attenuates immobility in forced swim tests in animal models of depression to a greater extent than several other commonly used antidepressants. In a six-week open label uncontrolled study, duloxetine was evaluated in patients with a history of depression. Duloxetine was effective in treating depression as determined by marked reduction in Hamilton Depression Rating scores. Adverse effects reported during duloxetine treatment were minor and similar to those of other antidepressants. In an eight-week multicenter, double-blind, placebo-controlled study in patients with a major depressive disorder, duloxetine was effective as an antidepressant, particularly in patients with greater symptom severity. Only limited data are available regarding the pharmacokinetic profile of duloxetine in humans, although a half-life of 10 to 15 h has been reported. Studies conducted in healthy human subjects confirm the preclinical profile of duloxetine as an inhibitor of 5-HT and NE reuptake. Taken together, existing data suggest that duloxetine is a novel and effective antidepressant.

Abnormal Prolactin Response May Predict Recurrent Depression

Abnormal Prolactin Response May Predict Recurrent Depression

Studies towards the next generation of antidepressants. Part 1: indolylcyclohexylamines as potent serotonin reuptake inhibitors

A series of indolylcyclohexylamines possessing potent and selective serotonin reuptake inhibition is reported. The most interesting compounds proved to have subnanomolar 5-HT transporter activity, and exhibited moderate 5-HT1A affinity.

The selective serotonin reuptake inhibitor sertraline: its profile and use in psychiatric disorders.

The naphthylamine derivative sertraline is a potent and selective inhibitor of serotonin reuptake into presynaptic terminals. Sertraline has a linear pharmacokinetic profile and a half-life of about 26 h. Its major metabolite, desmethylsertraline does not appear to inhibit serotonin reuptake. Sertraline mildly inhibits the CYP2D6 isoform of the cytochrome P450 system but has little effect on CYP1A2, CYP3A3/4, CYP2C9, or CYP2C19. It is, however, highly protein bound and may alter blood levels of other highly protein bound agents. Sertraline is a widely used serotonin reuptake inhibitor that has been shown to have both antidepressant and antianxiety effects. Many clinical trials have demonstrated its efficacy in depression compared with both placebo and other antidepressant drugs. Its efficacy has also been demonstrated in randomized, controlled trials of patients with obsessive-compulsive disorder, panic disorder, social phobia, and premenstrual dysphoric disorder. In short-term, open-label studies it has appeared efficacious and tolerable in children and adolescents and in the elderly, and data are positive for its use in pregnant or lactating women. Typical side effects include gastrointestinal and central nervous system effects as well as treatment-emergent sexual dysfunction; withdrawal reactions may be associated with abrupt discontinuation of the agent. The safety profile of sertraline in overdose is very favorable. Sertraline's efficacy for both mood and anxiety disorders, relatively weak effect on the cytochrome P450 system, and tolerability profile and safety in overdose are factors that contribute to make it a first-line agent for treatment in both primary and tertiary care settings.

Reactivity of serotonin in whole blood: relationship with drug response in obsessive-compulsive disorder

Background: Obsessive-compulsive disorder responds almost only to potent serotonin reuptake inhibitors. Previous studies have suggested a relation between serotonergic function and clinical outcome in serotonin reuptake inhibitor treatment of obsessive–compulsive disorder. Methods: In a randomized, double-blind trial, comparing clomipramine, paroxetine, and a placebo in obsessive–compulsive disorder, serotonin levels in whole blood (WB–5-HT) were measured at baseline, after 1 week, and after 4 weeks of treatment and related to clinical outcome in 36 patients. Results: In patients treated with serotonin reuptake inhibitors there was a pronounced decrease of WB–5-HT, variable after 1 week and uniformly maximal after 4 weeks. The decrease of WB–5-HT after 1 week of serotonin reuptake inhibitor treatment correlated negatively with clinical outcome after 12 weeks ( r = −.61, p = .0006); hence, patients with slower WB–5-HT reactivity eventually responded better to treatment. Baseline WB–5-HT, but not WB–5-HT reactivity, was related to season. Depression, autistic traits, and previous serotonin reuptake inhibitor treatment predicted nonresponse. Conclusions: A fast decrease of WB–5-HT was associated with poor clinical outcome. This may be related to faster serotonin efflux from platelets, which has previously been linked to autism. Further studies are necessary to identify the underlying mechanism and discern whether serotonin reuptake inhibitor–induced WB–5-HT decrease is clinically useful.

Fluoxetine: a review of its therapeutic potential in the treatment of depression associated with physical illness.

Fluoxetine is a potent and selective inhibitor of neuronal serotonin (5-hydroxytryptamine) reuptake. Fluoxetine reduces food, energy and carbohydrate intake and increases resting energy expenditure, which may account for the moderate and transient bodyweight loss observed with its use. Glucose tolerance and/or hypoglycaemia in patients with type 2 diabetes mellitus improve with fluoxetine therapy. The ability of fluoxetine to inhibit cytochrome P450 (CYP) isoenzymes (CYP2D6, CYP2C and CYP3A4), is potentially important for patients with physical illness who may be taking multiple concomitant medications. Fluoxetine was more effective than placebo in 2 double-blind, randomised trials, and according to limited data appears to be equally effective compared with other SSRIs and tricyclic antidepressants (TCAs), in the treatment of depression in patients with HIV/AIDS. The efficacy of fluoxetine is also superior to that of placebo in the treatment of depression in patients with diabetes mellitus and stroke as shown in double-blind randomised trials, although its efficacy relative to that of nortriptyline in stroke is uncertain. Fluoxetine had similar efficacy to that of desipramine in patients with cancer, with improved Hamilton Depression Rating Scale and quality-of-life scores from baseline; however, the drug was not more effective than placebo in a double-blind randomised trial. Medically healthy individuals tolerate fluoxetine well. Like other SSRIs, fluoxetine lacks the anticholinergic, cardiovascular, sedative and weight-increasing properties of TCAs, and is safer in overdose than TCAs and monoamine oxidase inhibitors. Rates of sexual dysfunction and suicidal ideation with fluoxetine appear similar to those seen with other SSRIs. Fluoxetine has shown superior efficacy compared with placebo in the treatment of depression in patients with HIV/AIDS, diabetes mellitus or stroke; however, it has not significantly improved depressive symptoms versus placebo in patients with cancer. The efficacy of fluoxetine appears similar to that of desipramine in patients with stroke, cancer or HIV, and is similar to that of sertraline or paroxetine in patients with HIV/AIDS; comparisons with nortriptyline give equivocal results. The potential for drug interactions with fluoxetine use should be carefully considered because most patients with comorbid physical illness will be receiving multiple comedications. Although fluoxetine has proved effective as an antidepressant in this population in several clinical trials, its drug interaction profile and long half-life are a potential limitation, and these properties should be carefully considered in relation to the status of each patient.