Clinically significant drug interactions with newer antidepressants

After the introduction of selective serotonin reuptake inhibitors (SSRIs), other newer antidepressants with different mechanisms of action have been introduced in clinical practice. Because antidepressants are commonly prescribed in combination with other medications used to treat co-morbid psychiatric or somatic disorders, they are likely to be involved in clinically significant drug interactions. This review examines the drug interaction profiles of the following newer antidepressants: escitalopram, venlafaxine, desvenlafaxine, duloxetine, milnacipran, mirtazapine, reboxetine, bupropion, agomelatine and vilazodone. In general, by virtue of a more selective mechanism of action and receptor profile, newer antidepressants carry a relatively low risk for pharmacodynamic drug interactions, at least as compared with first-generation antidepressants, i.e. monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). On the other hand, they are susceptible to pharmacokinetic drug interactions. All new antidepressants are extensively metabolized in the liver by cytochrome P450 (CYP) isoenzymes, and therefore may be the target of metabolically based drug interactions. Concomitant administration of inhibitors or inducers of the CYP isoenzymes involved in the biotransformation of specific antidepressants may cause changes in their plasma concentrations. However, due to their relatively wide margin of safety, the consequences of such kinetic modifications are usually not clinically relevant. Conversely, some newer antidepressants may cause pharmacokinetic interactions through their ability to inhibit specific CYPs. With regard to this, duloxetine and bupropion are moderate inhibitors of CYP2D6. Therefore, potentially harmful drug interactions may occur when they are coadministered with substrates of these isoforms, especially compounds with a narrow therapeutic index. The other new antidepressants are only weak inhibitors or are not inhibitors of CYP isoforms at usual therapeutic concentrations and are not expected to affect the disposition of concomitantly administered medications. Although drug interactions with newer antidepressants are potentially, but rarely, clinically significant, the use of antidepressants with a more favourable drug interaction profile is advisable. Knowledge of the interaction potential of individual antidepressants is essential for safe prescribing and may help clinicians to predict and eventually avoid certain drug combinations.     

Tricyclic antidepressant pharmacology and therapeutic drug interactions updated

New data on the pharmacology of tricyclic antidepressants (TCAs), their affinities for human cloned CNS receptors and their cytochrome P450 enzyme inhibition profiles, allow improved deductions concerning their effects and interactions and indicate which of the TCAs are the most useful. The relative toxicity of TCAs continues to be more precisely defined, as do TCA interactions with selective serotonin reuptake inhibitors (SSRIs). TCA interactions with monoamine oxidase inhibitors (MAOIs) have been, historically, an uncertain and difficult question, but are now well understood, although this is not reflected in the literature. The data indicate that nortriptyline and desipramine have the most pharmacologically desirable characteristics as noradrenaline reuptake inhibitors (NRIs), and as drugs with few interactions that are also safe when coadministered with either MAOIs or SSRIs. Clomipramine is the only available antidepressant drug that has good evidence of clinically relevant serotonin and noradrenaline reuptake inhibition (SNRI). These data assist drug selection for monotherapy and combination therapy and predict reliably how and why pharmacodynamic and pharmacokinetic interactions occur. In comparison, two newer drugs proposed to have SNRI properties, duloxetine and venlafaxine, may have insufficient NRI potency to be effective SNRIs. Combinations such as sertraline and nortriptyline may therefore offer advantages over drugs like venlafaxine that have fixed ratios of SRI/NRI effects that are not ideal. However, no TCA/SSRI combination is sufficiently safe to be universally applicable without expert knowledge. Standard texts (e.g. the British National Formulary) and treatment guidelines would benefit by taking account of these new data and understandings.     

Current trends in the development of new antidepressants

Early antidepressant medications e.g. tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are effective because they enhance either noradrenergic or serotonergic mechanisms, or both. Unfortunately, these compounds block cholinergic, histaminergic and alpha-1-adrenergic receptor sites, interact with a number of other medications and bring about numerous undesirable side effects. Several chemically unrelated agents have been developed and introduced in the past decade to supplement the early antidepressants. These include selective inhibitors of the reuptake of serotonin (the selective serotonin reuptake inhibitors (SSRIs)) or noradrenaline (reboxetine) or both (SNRIs: milnacipran and venlafaxine), as well as drugs with distinct neurochemical profiles such as mirtazapine, nefazodone, moclobemide and tianeptine. All these newer compounds are the results of rational developmental strategies to find drugs that were as effective as the TCAs but of higher safety and tolerability profile. In spite of the remarkable structural diversity, most currently introduced antidepressants are monoamin based and modulating monoamine activity as a therapeutic strategy continues to dominate antidepressant research. It must be emphasised, however, that these newer antidepressants are far from the ideal ones, also resulting in undesirable side effects and requiring 2-6 weeks of treatment to produce therapeutic effect. Furthermore, approximately 30% of the population do not respond to current therapies. An important new development has been the emergence of potential novel mechanisms of action beyond the monoaminergic synapse. The results of recent novel developmental approaches have suggested that modulation of N-methyl-D-aspartate (NMDA), neuropeptide (substance P and corticotrophin-releasing factor) receptors and the intracellular messenger system may provide an entirely new set of potential therapeutic targets. This paper discusses the advances from monoamine-based treatment strategies and looks at the future developments in the treatment of depression.     

Antidepressant-induced hepatotoxicity

Depression is a chronic, severe and increasingly prevalent illness associated with substantial morbidity, mortality and healthcare costs. Antidepressant drugs, the cornerstone of depression treatment, are not devoid of adverse effects, including hepatotoxicity. To review the risk of liver toxicity related to major antidepressants, the authors have followed structural criteria focusing on the underlying mechanism presumably involved and the role of particular chemical structures. The clinicopathological expression goes from transient increases in liver enzymes to fulminant liver failure. Classical antidepressants such as monoamine oxidase inhibitors (MAOIs) or tricyclic antidepressants (TCAs) seem to have the highest potential to induce liver damage compared with the newer drugs such as selective serotonin re-uptake inhibitors (SSRIs). The potential for severe hepatotoxicity associated with nefazodone is stressed. Guidelines for therapy and prevention of antidepressant-induced hepatotoxicity are also discussed.     

Metabolic drug interactions between antidepressants and anticancer drugs: focus on selective serotonin reuptake inhibitors and hypericum extract

Different antidepressant drugs are currently used for the treatment of depression in cancer patients, such as second-generation antidepressants and, recently, the extracts of Hypericum perforatum. These agents are susceptible to metabolically-based drug interactions with anticancer drugs. The aim of the present article is to provide an updated review of clinically relevant metabolic drug interactions between selected anticancer drugs and antidepressants, focusing on selective serotonin reuptake inhibitors (SSRIs) and Hypericum extract. SSRIs can cause pharmacokinetic interactions through their in vitro ability to inhibit one or more cytochrome P450 isoenzymes (CYPs). SSRIs differ in their potential for metabolic drug interactions with anticancer drugs. Fluoxetine and paroxetine are potent inhibitors of CYP2D6 and administration of these SSRIs reduces the clinical benefit of an anticancer drug, such as tamoxifen, by decreasing the formation of active metabolites of this drug. Women with breast cancer who receive paroxetine in combination with tamoxifen are at increased risk for death. Other SSRIs, including citalopram, escitalopram, are weak or negligible inhibitors of CYP2D6 and are less likely to interact with anticancer drugs, while sertraline causes significant inhibition of this isoform only at high doses. Hypericum extract, by inducing both the CYP3A4 and the P-glycoprotein (P-gp), can reduce the plasma concentrations of different antineoplastic agents such as imatinib, irinotecan and docetaxel, thus reducing the clinical efficacy of these drugs. Although these interactions are often predictable, the use of fluoxetine, paroxetine and Hypericum extract should be avoided in cancer patients.     

Antidepressants and their effect on sleep

Given the relationship between sleep and depression, there is inevitably going to be an effect of antidepressants on sleep. Current evidence suggests that this effect depends on the class of antidepressant used and the dosage. The extent of variation between the effects of antidepressants and sleep may relate to their mechanism of action. This systematic review examines randomised-controlled trials (RCTs) that have reported the effect that antidepressants appear to have on sleep. RCTs are not restricted to depressed populations, since several studies provide useful information about the effects on sleep in other groups. Nevertheless, the distinction is made between those studies because the participant's health may influence the baseline sleep profiles and the effect of the antidepressant. Insomnia is often seen with monoamine oxidase inhibitors (MAOIs), with all tricyclic antidepressants (TCAs) except amitriptyline, and all selective serotonin reuptake inhibitors (SSRIs) with venlafaxine and moclobemide as well. Sedation has been reported with all TCAs except desipramine, with mirtazapine and nefazodone, the TCA-related maprotiline, trazodone and mianserin, and with all MAOIs. REM sleep suppression has been observed with all TCAs except trimipramine, but especially clomipramine, with all MAOIs and SSRIs and with venlafaxine, trazodone and bupropion. However, the effect on sleep varies between compounds within antidepressant classes, differences relating to the amount of sedative or alerting (insomnia) effects, changes to baseline sleep parameters, differences relating to REM sleep, and the degree of sleep-related side effects.     

Risk of seizures associated with psychotropic medications: emphasis on new drugs and new findings

Psychotropic medications in the classes of antidepressants, antipsychotics and mood stabilisers have been recognised in the literature and clinical settings as having high epileptogenic potential. Among these three classes, clozapine, tricyclic antidepressants (TCAs) and lithium are agents that clinicians have historically recognised as precipitants of drug-induced seizures. There are few reports that review the epileptogenic risk of newer psychotropic agents; in this qualitative review, the authors provide an update on the most recently published reports on seizures associated with antidepressants, antipsychotics, mood stabilisers, anxiolytics and sedative-hypnotics. In general, the epileptogenic risks of the newer psychotropic agents appear to be quite low as long as dosing strategies are consistent with recommended guidelines. Whilst newer psychotropic medications appear to be safe in patients with epilepsy, few studies have specifically addressed this population. In addition, the potential for drug interactions between antiepileptic drugs and psychotropics may be substantial with certain agents. For example, many psychotropes are both substrates and inhibitors of cytochrome P450 (CYP450) isoenzymes, whilst many antiepileptic drugs are both substrates and inducers of CYP450 activity. Every attempt should be made to minimise potential interactions when these agents are concomitantly administered.     

Risk of seizures associated with psychotropic medications: emphasis on new drugs and new findings

Psychotropic medications in the classes of antidepressants, antipsychotics and mood stabilisers have been recognised in the literature and clinical settings as having high epileptogenic potential. Among these three classes, clozapine, tricyclic antidepressants (TCAs) and lithium are agents that clinicians have historically recognised as precipitants of drug-induced seizures. There are few reports that review the epileptogenic risk of newer psychotropic agents; in this qualitative review, the authors provide an update on the most recently published reports on seizures associated with antidepressants, antipsychotics, mood stabilisers, anxiolytics and sedative-hypnotics. In general, the epileptogenic risks of the newer psychotropic agents appear to be quite low as long as dosing strategies are consistent with recommended guidelines. Whilst newer psychotropic medications appear to be safe in patients with epilepsy, few studies have specifically addressed this population. In addition, the potential for drug interactions between antiepileptic drugs and psychotropics may be substantial with certain agents. For example, many psychotropes are both substrates and inhibitors of cytochrome P450 (CYP450) isoenzymes, whilst many antiepileptic drugs are both substrates and inducers of CYP450 activity. Every attempt should be made to minimise potential interactions when these agents are concomitantly administered.     

Expanding the horizons of depression: beyond the monoamine hypothesis

The monoamine hypothesis has dominated our understanding of depression and of pharmacological approaches to its management and it has produced several generations of antidepressant agents, ranging from the monoamine oxidase inhibitors (MAOIs), through tricyclics (TCAs) and selective serotonin reuptake inhibitors (SSRIs), to the recently introduced selective noradrenaline reuptake inhibitor (NARI), reboxetine. Greater receptor selectivity has improved tolerability, but not efficacy, when newer compounds are compared with the original tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors. Essentially, the newer antidepressants have the same distinguishing feature as older ones, i.e. acute enhancement of monoaminergic neurotransmission. The monoamine hypothesis cannot conclusively link the acute biochemical action of antidepressants on monoamine levels with their delayed clinical effect of 10-14 days, nor can it explain the mode of action of antidepressants that are effective despite being very weak inhibitors of monoaminergic transmission (e.g. iprindole) or, incongruously, enhancing monoamine uptake (e.g. tianeptine). Compared with other fields of medicine, there has been a lack of progress in understanding the pathophysiology of depression and producing truly novel antidepressant agents. Other biological approaches to depression, such as overactivity of the hypothalamic-pituitary-adrenal axis, hippocampal neural plasticity in response to stress, and the link between the inflammatory response and depression, offer new approaches to finding pharmacological agents, aided by improved techniques for visualising the human brain, better animal models, and increased knowledge of human markers of depression. Copyright 2001 John Wiley & Sons, Ltd.     

Section Review Central & Peripheral Nervous Systems: New antidepressant agents: Recent pharmacological developments leading to improved efficacy

The disadvantages of the standard tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), in terms of side-effects and fatal overdose, led to the development and release of seven new antidepressants in the USA in the past eight years with approximately another ten in various stages of development. This paper will focus on how recent advances in biochemistry and kinetics have led to improved efficacy. In particular, the more specific 5-HT agents appear effective for ‘typical’ depression and pain; the less specific ones for depression associated with obsessive-compulsive disorder. The selective serotonin reuptake inhibitors (SSRIs) are particularly suited for treatment of depression associated with diabetes mellitus; the serotonin and norepinephrine reuptake inhibitor (SNRI), venla-faxine, for resistant depression; and bupropion, for atypical depression. The serotonin receptor modulator (SRM), nefazodone, in contrast, is particularly suited for the treatment of depression associated with insomnia because of its combined SSRI and post-synaptic 5-HT_2A/C receptor antagonist effects. In terms of kinetics, important factors include, particularly: elimination half-lives, linearity of kinetics, therapeutic blood levels, effects on hepatic microen-zymes, and effects on memory and alertness. Discussion of these seven antidepressants is followed by a brief review of knowledge concerming other potential antidepressants in development.     

Charleston Antidepressant Drug Interactions Surveillance Program (CADISP)

A prospective antidepressant drug interaction surveillance program was established and collected data for over 4 years in Charleston, SC (Charleston Antidepressant Drug Interactions Surveillance Program, CADISP). One hundred and seventy patients were enrolled. The plasma concentrations and/or clinical effects of drug combinations were monitored in psychiatric patients who received therapy with a selective serotonin reuptake inhibitor (SSRI) or one of the other newer antidepressants (nefazodone, venlafaxine) when combined with other drugs metabolized by the cytochrome P-450 (CYP) enzyme system. Patient data were evaluated to estimate the occurrence and significance of antidepressant-induced metabolic drug interactions. Plasma drug concentrations in the presence and absence of treatment with an antidepressant served as the primary assessment variable. Contrary to the hypothesis that pharmacokinetic drug-drug interactions occur but go undetected, little evidence was found for occultly occurring drug interactions with newer antidepressants. The presence of commonly predicted drug interactions was documented. These data do not eliminate the need for caution when prescribing antidepressants with the potential for causing metabolic interactions, but do help allay the fear that such interactions are highly prevalent and routinely hazardous.     

Selective serotonin reuptake inhibitors: a review of efficacy and tolerability in depression

Selective serotonin reuptake inhibitors (SSRIs) are now generally regarded as effective and better tolerated alternatives to tricyclic antidepressants (TCAs) for the treatment of depression. SSRIs also seem to be as well tolerated as moclobemide, mirtazapine, venlafaxine, reboxetine and nefazodone and show comparable efficacy. Minor differences have been observed between some SSRIs and some of the newer antidepressants but these findings are far from conclusive. Widespread use of the SSRIs has highlighted some unforseen adverse effects associated with SSRIs, namely hyponatraemia, EPSE and sexual dysfunction. Overall, differences in efficacy and tolerability between individual SSRIs are small and clinically insignificant.     

Antidepressant-drug interactions are potentially but rarely clinically significant.

The salient pharmacologic features of the selective serotonin reuptake inhibitors (SSRIs) discovered in the late 1980s included an in vitro ability to inhibit various cytochrome P450 enzymes (CYPs). Differences in potency among the SSRIs for CYP inhibition formed the basis of a marketing focus based largely on predictions of in vivo pharmacokinetic drug interactions from in vitro data, conclusions derived from case reports, and the extrapolation of the results of pharmacokinetic studies conducted in healthy volunteers to patients. Subsequently introduced antidepressants have undergone a similar post hoc scrutiny for potential drug-drug interactions. Concern for the untoward consequences of drug interactions led the FDA to publish guidance for the pharmaceutical industry in 1997 recommending that in vitro metabolic studies be conducted early in the drug development process to evaluate inhibitory properties toward the major CYPs. However, the prevalence of clinically significant enzyme inhibition interactions occurring during antidepressant treatment remains poorly defined despite millions of exposures. Although lack of evidence does not equate to evidence of absence, sparse epidemiological and post-marketing surveillance data do not substantiate a conclusion that widespread morbidity results from antidepressant-induced drug interactions. This commentary discusses points of uncertainty and controversy in the field of drug interactions, notes areas where inadequate data exist, and suggests explanations for a low prevalence of serious interactions. The conclusion is drawn that drug interactions from CYP inhibition caused by the newer antidepressants are potentially, but rarely, clinically significant.     

Monoamine oxidase inhibitors: reversible and irreversible.

Coincident with and in part fueling advances in diagnostic nosology and drug development, the recent resurgence of interest in monoamine oxidase inhibitors (MAOIs) is reviewed. Accidentally discovered nearly 40 years ago as the first true antidepressants, the MAOIs soon fell into disfavor due to concerns about toxicity and seemingly lesser efficacy compared with the newer tricyclic compounds. Now that we have better understanding of the nature of the hypertensive and hyperpyrexic interactions of MAOIs with other substances, these medications have assumed a role in the treatment of nonendogenous depressive and anxiety syndromes, especially in operationally defined "atypical depression." The discovery of two MAO isoenzymes has resulted in a new generation of selective inhibitors in the search for enhanced efficacy (i.e., clorgyline) or safety (i.e., l-deprenyl). Most promising is the emerging class of reversible selective MAO-type A inhibitors, such as moclobemide, which combine antidepressant potency with freedom from the risk of dangerous tyramine-type adverse interactions.     

氟西汀的药代动力学及其与CYP450酶的作用

氟西汀是近年来开发的一种新型 5 羟色胺重摄取抑制剂 ,它通过选择性抑制突触间 5 羟色胺 (5 HT)的重摄取和代谢 ,增加突触间 5 HT的传递而发挥作用。氟西汀由细胞色素P45 0 (CYP45 0 )酶进行氧化代谢 ,现已证明CYP2C9,CYP2C19和CYP2D6是介导氟西汀N 去甲基代谢的主要CYP45 0同工酶。由于氟西汀及代谢产物去甲氟西汀分别为CYP2D6、CYP3A4、CYP2C19和CYP2C9的抑制剂 ,因此它可与经这些CYP同工酶催化代谢的药物产生明显的相互作用 ;从而导致不同个体间的药代动力学差异和疗效差异。     

Rational Drug Use in the Treatment of Depression

New drugs are being developed for the management of depression in response to the growing awareness of the prevalence and disability associated with the disorder and the need for agents with improved side effect profiles. All antidepressants are equally effective for treating uncomplicated unipolar depression without psychotic features. For patients with atypical depression with prominent anxiety, agitation, sleep loss, and irritability, monoamine oxidase inhibitors are the first choice. Data are accumulating supporting the efficacy of selective serotonin reuptake inhibitors (SSRIs) in these depressive subtypes. Factors to consider when choosing an antidepressant include spectrum of adverse effects, long-term tolerability dosing schedule, clinically significant drug interactions, underlying medical conditions, earlier response to therapy, and pharmacoeconomics. Based on these criteria, it is suggested that a trial with the SSRIs be attempted first. Venlafaxine and nefazodone are newer agents with mechanisms of action that have advantages over tricyclic antidepressants and monoamine oxidase inhibitors. Choosing a drug that is effective, tolerable, and convenient will improve the likelihood of achieving and maintaining a full remission. It will also decrease the morbidity and mortality of this very treatable disease.     

Citalopram in the treatment of depression and other potential uses in psychiatry.

During the past decade, treatment options for depression have increased with the introduction of new agents. Older agents, such as tricyclic antidepressants and monoamine oxidase inhibitors, increase noradrenergic and serotonergic neurotransmission. Attempts to separate antidepressant effects from adverse effects led to the development of selective serotonin reuptake inhibitors (SSRIs). Citalopram is the newest SSRI to be marketed in the United States. Of all SSRIs on the market, it is the most selective for serotonin reuptake pump. Its efficacy in treating depression was evident in both placebo-controlled and comparator trials. In addition, citalopram was studied in the treatment of other psychiatric disorders. The agent has less inhibition of cytochrome P450 enzymes than other SSRIs, possibly giving it a lower potential for drug interactions.     

Severe depression: is there a best approach?

A major depressive episode can be categorised as severe based on depressive symptoms, scores on depression rating scales, the need for hospitalisation, depressive subtypes, functional capacity, level of suicidality and the impact that the depression has on the patient. Several biological, psychological and social factors, and the presence of comorbid psychiatric or medical illnesses, impact on depression severity. A number of factors are reported to influence outcome in severe depression, including duration of illness before treatment, severity of the index episode, treatment modality used, and dosage and duration of and compliance with treatment. Potential complications of untreated severe depression include suicide, self-mutilation and refusal to eat, and treatment resistance. Several antidepressants have been studied in the treatment of severe depression. These include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline (norepinephrine) reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin 5-HT(2) receptor antagonists, monoamine oxidase inhibitors, and amfebutamone (bupropion). More recently, atypical antipsychotics have shown some utility in the management of severe and resistant depression. Data on the differential efficacy of TCAs versus SSRIs and the newer antidepressants in severe depression are mixed. Some studies have reported that TCAs are more efficacious than SSRIs; however, more recent studies have shown that TCAs and SSRIs have equivalent efficacy. There are reports that some of the newer antidepressants may be more effective than SSRIs in the treatment of severe depression, although the sample sizes in some of these studies were small. Combination therapy has been reported to be effective. The use of an SSRI-TCA combination, while somewhat controversial, may rapidly reduce depressive symptoms in some patients with severe depression. The combination of an antidepressant and an antipsychotic drug is promising and may be considered for severe depression with psychotic features. Although the role of cognitive behaviour therapy (CBT) in severe depression has not been adequately studied, a trial of CBT may be considered in severely depressed patients whose symptoms respond poorly to an adequate antidepressant trial, who are intolerant of antidepressants, have contraindications to pharmacotherapy, and who refuse medication or other somatic therapy. A combination of CBT and antidepressants may also be beneficial in some patients. Electroconvulsive therapy (ECT) may be indicated in severe psychotic depression, severe melancholic depression, resistant depression, and in patients intolerant of antidepressant medications and those with medical illnesses which contraindicate the use of antidepressants (e.g. renal, cardiac or hepatic disease).     

Unmet needs in the pharmacological management of depression

Newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), selective noradrenaline reuptake inhibitors (NRIs) and drugs acting on both serotonin and noradrenaline, represent a clinically significant advance over the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors. Nevertheless, all current pharmacological treatments for depression fall somewhat short of the 'ideal', and unmet needs remain in the pharmacological management of depression. In general, current antidepressants differ little in terms of efficacy. However, in terms of tolerability, SSRIs appear to offer clear advantages over older therapies. For example, the proportion of patients who discontinue treatment because of adverse events and the risk of fatal toxicity both appear to be lower with SSRIs, compared with TCAs. Some adverse events, however, such as sexual dysfunction and nausea (typical serotonergic side effects), tend to be more frequent with SSRIs. Also, individual SSRIs appear to differ in the likelihood that they will be associated with these side effects. However, no clear advantage emerges for any one SSRI over another, and the current recommendation is that the anticipated side-effect profile should be tailored to the patient. Current pharmacoeconomic data do not appear to favour any antidepressant over another, with no cost benefits associated with prescribing TCAs instead of SSRIs.The refinement of current drugs arising from the introduction of their active enantiomers may translate into clinical benefit, bringing closer the 'ideal' antidepressant. Potential benefits of a single enantiomer versus the racemate in the management of depression include: a reduction in the total dose, while maintaining desired outcomes, as well as a possible greater efficacy, dose for dose,simpler assessment of dose-response relationships,a reduction in pharmacokinetic and pharmacodynamic variability between patients, anda reduction in any toxicity arising from the inactive stereoisomer. However, these benefits remain to be proved in clinical trials and naturalistic studies. Further refinement of the benefit:risk ratio of current 'gold standard' drugs may go some way to addressing the shortfalls in existing antidepressant therapy. Copyright 2001 John Wiley & Sons, Ltd.