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Background: The purpose of this paper is to use demographic and clinical data from a large diverse group of outpatients diagnosed with non-psychotic major depression to investigate the validity of the DSM-IV concept of melancholic depression., Methods: Baseline clinical and demographic data were collected on 1500 outpatients (1456 of whom melancholia could be determined) with non-psychotic major depressive disorder (MDD) participating in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Depressive symptom severity was assessed by clinical telephone interview using the 17-item Hamilton Rating Scale for Depression (HRS-D17) and the 30-item Inventory of Depressive Symptomatology (IDS-C30). The types and degrees of concurrent psychiatric symptoms were measured using a self report, the Psychiatric Diagnostic Screening Questionnaire (PDSQ), by recording the number of items relevant to each diagnostic category endorsed by study participants., Results: Adjusting for severity of depression (as measured by the total HRS-D17 scores), no differences were found in the rate of melancholic depression by race, marital status, education, employment status, family history of depression, primary care versus specialty care, monthly income, and degree of psychiatric and medical co-morbidity. Melancholic depression was significantly more likely in men than women. Melancholic depression after adjustment for severity was associated with a slightly younger age at study entry, as well as with greater illness severity, and slightly shorter duration of current episode. Hispanic ethnicity was associated with lower melancholic depression rates at the .06 level of significance., Conclusions: Among outpatients with MDD, melancholic features were less likely in Hispanic patients, but more likely in slightly younger patients and in men. Melancholic features were also related to a slightly shorter current episode. These findings are consistent with the notion that external socio-demographic factors do not play an important role in the pathophysiology of melancholic depression.

Biological interactions are stereoselective; thus the interactions of drugs with corresponding biological targets must also be stereoselective. However, many drugs used today are racemic mixtures. For example, approximately 25% or 1 in 4 marketed drugs are mixtures of agents (racemates) rather than single chemical entities (enantiomers). One of these enantiomers can be inactive or even counterproductive to the therapeutic use of the drug: either by reducing the efficacy of the active enantiomer or by causing unnecessary tolerability problems or even toxicity through differential pharmacodynamics. The presence of a therapeutically inactive or counterproductive enantiomer can also complicate the pharmacokinetics of the active enantiomer and the interpretation of the therapeutic drug monitoring (e.g., plasma levels) if the assay is not capable of separately quantitating the two enantiomers. This article reviews the history of stereoisomers and the relevant pharmacological principles, then discusses recent changes in rules governing drug approval and the potential advantages to the patient and the manufacturer of developing single enantiomers.

Objective: Clinical trials are indispensable to drug approval process. This research examined the effect of a specific study criteria on recruitment and generalizability of the results., Methods: The following were reviewed: (a) the usual inclusion and exclusion criteria for the antipsychotic trials performed at the Institute; (b) epidemiologic data, to determine the effect of study criteria on the target population; and (c) the recruitment procedures/strategies used to identify potential candidates. A survey was conducted to determine the percentage of schizophrenic patients in a conventional outpatient psychiatric clinic conforming to the usual enrollment criteria for antipsychotic trials., Results: Intensive recruitment efforts in a general population of 3.6 million would have been expected to yield only 632 eligible subjects out of 36,000 suffering from schizophrenia. Out of 632, only 50 contacted the research site after an intensive recruitment effort. From those 50, 30 were excluded during a telephone interview. Of the 20 remaining, 6 were excluded for a variety of reasons during a face-to-face interview. Thus, only 14 subjects out of a population of 3.6 million met the study criteria., Conclusions: These results emphasize the rarified nature of patients-volunteers who enter a clinical trial. Inclusion and exclusion study criteria can severely restrict the number of eligible subjects, dictate recruitment strategies, and in turn affect generalizability of the results.

Patients with acute psychosis often exhibit agitation, which can be distressing and hazardous to others as well as to the patient. In such psychiatric emergencies, intramuscular antipsychotic agents can be easier to administer than oral formulations, and they have the added advantage of more rapid absorption and a faster onset of action. However, intramuscular formulations of conventional antipsychotics, which have been the standard treatment, are associated with acute dystonia and other movement disorder-related adverse events. Ziprasidone is the first atypical antipsychotic to be clinically available in both intramuscular and oral formulations in the US. The intramuscular formulation of ziprasidone, ziprasidone mesylate, uses sulfobutylether beta-cyclodextrin to solubilise the drug by complexation. The pharmacokinetics of intramuscular ziprasidone include rapid attainment of therapeutic drug level (time to reach peak serum concentration [tmax]

Aim: This open-label, multiple-dose trial investigated the effect of concurrent administration of donepezil HCl with risperidone on the pharmacokinetics (PK) and safety profiles of both drugs., Methods: Sixteen male patients with schizophrenia, who were receiving stable, physician-optimized risperidone (1-4 mg twice daily), and 15 healthy age- and weight-matched male controls, received donepezil HCl 5 mg daily for 7 days. Patients with schizophrenia remained on their physician-optimized dose of risperidone throughout the study. Pharmacokinetic parameters (C(max), t(max) and AUC) were assessed from plasma drug concentrations measured in blood collected before, during and after administration (for 12 h after risperidone on days 0 and 7, and for 24 h after donepezil HCl on day 7)., Results: The mean age of all the subjects was 38.5 years. Donepezil PK parameters were similar between patients taking donepezil HCl + risperidone (AUC(0-24 h) = 329.0 +/- 17.2 ng x h ml(-1)) and controls taking donepezil HCl alone (AUC(0-24 h) = 354.7 +/- 28.2 ng x h ml(-1)). Pharmacokinetic parameters for risperidone and 9-OH risperidone were not altered in patients with schizophrenia after 7 days of donepezil HCl administration (AUC(0-12 h) standardized by dose: risperidone = 59.6 +/- 16.3 ng.h ml(-1) at day 0, 56.0 +/- 15.8 ng x h ml(-1) at day 7; 9-OH risperidone = 162.1 +/- 19.2 ng x h ml(-1) at day 0, 163.3 +/- 15.0 ng x h ml(-1) at day 7). The most common adverse event in both treatment groups was diarrhoea (6/16 risperidone + donepezil HCl patients and 9/16 donepezil HCl only subjects). There were no significant changes in physical examination, ECG, vital signs or treatment-emergent abnormal laboratory values associated with either of the treatment regimens. No subject developed extrapyramidal side-effects following donepezil administration., Conclusions: These results suggest that once-daily dosing of 5 mg donepezil HCl does not alter the PK of risperidone in patients with schizophrenia. The combination of risperidone and donepezil HCl was well tolerated.

DDIs have important implications for managed care. They can adversely impact patient outcomes and can also have serious cost implications. The problem posed by unintended and adverse DDIs will continue to grow in importance as the complexity and uniqueness of medication regimens escalate in an aging population using increasingly sophisticated and varied pharmacological agents. In this paper, antidepressants and SSRIs in particular were used to illustrate these important points.

The efficacy and safety of a selective NK(1) antagonist, L-759274, was investigated in outpatients with diagnosis of major depressive disorder with melancholic features, following evidence obtained with the novel compound aprepitant that Substance P (NK(1)) antagonists may provide a unique mechanism of antidepressant activity. A randomized, double-blind placebo-controlled study was carried out. Patients, male or female, aged 18-60, scoring >/=25 points on total of first 17 items of 21-item Hamilton Depression Scale (HAMD), and scoring >/=4 (moderately ill) on Clinical Global Impressions-Severity Scale were randomized to oral L-759274 40 mg daily (n=66) or placebo (n=62) for 6 weeks. For patients receiving L-759274, improvement (mean decrease from baseline) in HAMD-17 total score was 10.7 points, compared with a mean 7.8 point improvement in patients receiving placebo (p<0.009). Mean scores for item 1 of HAMD-17 (depressed mood) also improved to a greater extent in the active group compared with the placebo group (0.3 points, p<0.058). Compared with placebo, mean scores on Clinical Global Impressions-Improvement Scale improved significantly by the end of the trial (p=0.009). L-759274 was generally safe and well-tolerated. The incidence of sexual side effects was on par with that observed in patients receiving placebo, and the incidences of gastrointestinal effects were low. Antidepressant actions have now been observed with two different highly selective NK(1) antagonists (aprepitant and L-759274). NK(1) antagonism is a replicated and generally well-tolerated antidepressant mechanism.

Objective: To evaluate the efficacy and safety of mirtazapine in depressed outpatients who have shown nonresponse or intolerance to selective serotonin reuptake inhibitor (SSRI) therapy., Method: In this open-label, 8-week study, the efficacy and safety of mirtazapine among 103 outpatients with DSM-IV major depressive disorder who had failed previous therapy with an SSRI (fluoxetine, paroxetine, or sertraline) were evaluated. The primary efficacy measure was the 17-item Hamilton Rating Scale for Depression (HAM-D-17), and safety assessments included reported adverse events, routine laboratory assessments, physical examinations, and assessments of vital signs. A 4-day washout period followed by mirtazapine treatment was compared with an immediate switch from the SSRI to mirtazapine., Results: Based on mean HAM-D-17 scores at endpoint and response rates of 48% based on the criterion of > or = 50% reduction in HAM-D-17 score, mirtazapine was found to be an effective treatment for a substantial proportion of patients for whom an SSRI was ineffective and/or poorly tolerated. Mirtazapine was well tolerated, with sedation and appetite increase/weight gain the most commonly reported adverse events. In addition, no difference in efficacy, safety, or tolerability was observed for patients undergoing an immediate switch from an SSRI (after having been tapered to the minimal effective dose) to mirtazapine, compared with those undergoing the imposition of a 4-day drug-free washout., Conclusion: These results suggest that an immediate switch to mirtazapine may be a valid therapeutic option among patients who cannot tolerate or do not respond to SSRIs.

The objective of this study was to assess in both young and elderly volunteers the pharmacokinetics of fluoxetine and norfluoxetine and effects on cytochrome P450 (CYP) 2C19. Male volunteers aged 18 to 40 years (N = 14) or older than 65 years (N = 16) received fluoxetine 20 mg/day for 6 weeks and fluoxetine 40 mg/day for an additional 6 weeks. Blood was drawn over a 24-hour period after the initial dose and after 6 weeks and 12 weeks to determine AUC0-24, Cmax, and tmax; weekly to evaluate predose levels (C0); and over a 3-week period after discontinuation to evaluate washout (t1/2). Mephenytoin was used to assess CYP2C19 activity before and after 6 weeks and 12 weeks of fluoxetine. Fluoxetine AUC0-24, C0, and Cmax did not differ in young and elderly subjects. The norfluoxetine C0 was 22% lower in elderly subjects (p < .05), with comparable decreases in AUC0-24 and Cmax. In the elderly volunteers, the t1/2 for fluoxetine was 25% longer (5.0 vs. 4.0 days) and for norfluoxetine was 33% longer (20 vs. 15 days), although variability and sample size precluded statistical significance. Fluoxetine dosing inhibited CYP2C19 activity in both age groups, increasing the (S)- to (R)-mephenytoin ratio 3- to 4-fold (p < .01). The half-lives of fluoxetine and norfluoxetine at 40 mg/day were longer than commonly reported in the literature and may be longer in elderly subjects. Fluoxetine substantially inhibited the metabolism of the CYP2C19 substrate (S)-mephenytoin.

Objective: To describe the pharmacokinetics and safety of nefazodone (NFZ) in depressed children and adolescents., Method: Depressed youths aged 7 to 17 years were eligible to participate. Intensive sampling for pharmacokinetic analyses of NFZ and 3 of its active metabolites was performed after single and multiple dose administration. Treatment was continued for 6 more weeks and titrated to maximize clinical response., Results: Twenty-eight patients were enrolled. Systemic exposure to NFZ and 3 metabolites was generally higher in children than adolescents. NFZ and metabolite disposition profiles showed high intra- and interpatient variability. Compared to published data in adults, the half-life of NFZ and 2 of its metabolites appears shorter in children and adolescents. Meta-chlorphenylpiperazine pharmacokinetic parameters were different in 5 patients determined to be poor metabolizers of cytochrome P450 2D6 (CYP2D6). NFZ was well tolerated, and administration was associated with significant reductions (p < .001) in depressive symptoms., Conclusions: The pharmacokinetics of NFZ in pediatric patients is highly variable. NFZ appears to be safe in this small, short-term study. Pediatric patients who are poor metabolizers of CYP2D6 do not appear to be at increased risk for NFZ-associated adverse events. Open-label treatment of NFZ is associated with reductions in depressive symptoms.

Background: Indirect evidence suggests that the antidepressant venlafaxine hydrochloride selectively inhibits serotonin (5-HT) uptake at low doses, whereas at high doses, it inhibits both 5-HT and norepinephrine (NE) uptake. We hypothesized that, in vivo, both high and low doses would inhibit the 5-HT uptake of platelets but that the higher dose would differentially blunt the pressor response to tyramine, a marker for NE uptake., Methods: Healthy male volunteers aged 18 to 45 years received either 75 mg or 375 mg of venlafaxine hydrochloride per day, the 5-HT uptake inhibitor sertraline hydrochloride (50 mg/d), or the NE uptake inhibitor maprotiline hydrochloride (150 mg/d) (n = 8 for each of 4 treatment groups). Changes in platelet 5-HT uptake and the pressor response to intravenous tyramine were assessed following the initial dose and after 1 and 2 weeks of drug administration., Results: Platelet 5-HT uptake was inhibited by venlafaxine across the dose range and by sertraline but not maprotiline. Inhibition was competitive, related to increases in affinity and not related to capacity. Steady-state drug levels were associated with a 5-HT uptake inhibition of 87% or more in subjects taking venlafaxine or sertraline. The pressor response to tyramine differentially distinguished maprotiline from sertraline and the low dose of venlafaxine but not from the high dose of venlafaxine., Conclusion: This study provides the first in vivo evidence in healthy humans that both 5-HT uptake and NE uptake inhibition are mechanisms of action sequentially engaged by venlafaxine over its clinically relevant dose range.

Despite evidence to support its potential benefit in clinical practice, therapeutic drug monitoring (TDM) is under-utilised and underdeveloped in the field of psychiatry. In antidepressant pharmacotherapy drug dose is emphasised as the critical treatment variable. However, dose in, and of, itself can be a strikingly misleading predictor of drug concentration and, hence, treatment effect. For antidepressant drugs, plasma concentrations at a given dose have been shown to vary in excess of 40-fold. The clinical relevance of this variability is that at a standard antidepressant dosage only some patients will have tissue drug concentrations associated with an optimal response whereas others will have either low, ineffective drug concentrations or unnecessarily high concentrations which may be poorly tolerated. Among clinicians and healthcare agencies there is an under-appreciation of the degree of pharmacokinetic variability found in patients and how that might impact on the patients response to pharmacotherapy. Hence there is a perception that TDM is an unnecessary, complicated and costly procedure. This is actually unfounded. There are data to suggest that TDM can favourably affect the outcome of antidepressant treatment by providing a rational alternative to the inherently slower, trial and error practice of dosage titration based on clinical response. It is unlikely that TDM will become a standard of care for all antidepressant agents and all patients. Therefore the question becomes for which antidepressant agents, for which patients and under what circumstances, is TDM more cost-effective than traditional dose titration. The use of TDM to optimise the efficient use of selected antidepressant agents could potentially free up healthcare resources to fund other equally deserving treatments. This article provides a discussion of the major classes of antidepressant drugs with regard to their pharmacological features that predict the utility of TDM in clinical practice. Recommendations are made for the practical application of TDM and the directions for further research.

This article summarizes the basic and clinical pharmacology of the available antidepressants to aid the busy primary care practitioner in anticipating and predicting the effects of different antidepressants on patients; choosing a specific antidepressant for each patient based on these effects; selecting a sequential antidepressant for the patient who has not benefited from a trial of a specific type of antidepressant, either because of inadequate effect or treatment-limiting adverse effects; and avoiding adverse drug interactions when choosing an antidepressant for patients on other drug therapy.

Tricyclic antidepressants have multiple sites of pharmacological actions which are responsible for their tolerability and toxicological problems as well as their efficacy. That fact has prompted the search for antidepressants with fewer sites of action. That search resulted in the serotonin selective reuptake inhibitors (SSRIs), with presumably only one site of action. Although the SSRIs are safer and better tolerated than the TCAs, a significant percentage of patients do not benefit from SSRIs. A group of "atypical antidepressants" including bupropion, nefazodone, and venlafaxine are known to have multiple sites of antidepressant action but do not interact at sites associated with side effects or tolerance. Thus this group of antidepressants present an important alternative to the SSRIs in the pharmacological therapy of depression. The basic pharmacological properties of bupropion, nefazodone, and venlafaxine are presented along with clinical profiles and the role of these three antidepressants in the pharmacotherapy of depression is discussed.

Objective: To document a case of serotonin syndrome associated with venlafaxine and fluoxetine that did not involve a monoamine oxidase inhibitor, and to examine the multiple factors, including pharmacodynamic and pharmacokinetic interactions, that likely caused this adverse drug reaction (ADR)., Case Summary: A 39-year-old white woman with depression and panic attacks was being treated with fluoxetine, trazodone, clonazepam, and cimetidine. After fluoxetine and clonazepam were abruptly discontinued, venlafaxine and lorazepam were started. Within 24 hours, she developed diaphoresis, tremors, slurred speech, myoclonus, restlessness, impaired thinking, and diarrhea. This constellation meets Sternbach's criteria for serotonin syndrome., Discussion: The possible contributors to this ADR are discussed, including a single drug effect (e.g., an idiosyncratic reaction to venlafaxine), a pharmacokinetic interaction, a pharmacodynamic interaction, a combined pharmacokinetic-pharmacodynamic interaction, and the patient' s panic disorder., Conclusions: As more serotonergic drugs are developed and used for psychiatric disorders, frequently in combination or close temporal proximity, clinicians must be aware of and consider the factors that may increase the risk of patients experiencing serotonin syndrome.

In 1993, it was first proposed that an important difference between selective serotonin reuptake inhibitors (SSRIs) was the degree of inhibition of the cytochrome P450 (CYP) enzyme 2D6 that they produced under usually dosing conditions (Preskorn, 1993). Specifically, fluoxetine and paroxetine, in contrast to sertraline, were identified as causing substantial increases in the plasma levels of coadministered drugs, which were principally dependent on CYP 2D6 for their metabolism. Over the next 5 years, this position was hotly contested (Preskorn and Nemeroff, 1997). However, an extensive body of research has now accumulated, which incontrovertibly supports the original position. This paper will reviews this research and extends the discussion to all five SSRIs and four other important CYP enzymes: 1A2, 2C9/10, 2C19, and 3A3/4.

In vitro studies have shown that fluoxetine and paroxetine are more potent inhibitors of cytochrome CYP2D6 than sertraline. The pharmacokinetics of desipramine when coadministered with the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline were studied in 24 healthy male volunteers (CYP2D6 extensive metabolizers). Desipramine (50 mg/day) was administered for 23 days in each phase of the crossover study with a 7-day drug-free period between phases. In addition, subjects were randomly assigned to receive concomitant paroxetine (20 mg/day on days 8 through 17 followed by 30 mg/day on days 18 through 20) or sertraline (50 mg/day on days 8 through 17 and 100 mg/day on days 18 through 20). SSRI treatments were switched between phases. After 10 days of coadministration at the lower dose, mean desipramine maximum concentration in plasma (Cmax) relative to baseline increased from 37.8 to 173 ng/mL (+358%) with paroxetine versus from 36.1 to 51.9 ng/mL (+44%) with sertraline; the mean desipramine 24-hour area under the concentration-time curve (AUC[24]) increased from 634 to 3,305 ng x h/mL (+421%) with paroxetine versus from 611 to 838 ng x h/mL (+37%) with sertraline; and the mean desipramine trough value (C0) increased from 18.5 to 113 ng/mL (+511%) with paroxetine versus from 18.3 to 21.8 ng/mL (+19%) with sertraline (all increases, p < 0.001). An approximately 10-fold increase in the Cmax and AUC(24) of paroxetine and an approximately 2-fold increase in these parameters for sertraline occurred simultaneously with the desipramine concentration changes. Thus, when coadministered with 50 mg/day desipramine, sertraline had significantly less pharmacokinetic interaction than paroxetine with desipramine at the recommended starting dosages of 50 mg/day and 20 mg/day, respectively.

Age-associated decreases in metabolism and elimination of drugs are sufficient to give one pause before prescribing drugs in the elderly particularly if multiple drugs are to be used. When one factors in concomitant drugs that may inhibit P450-mediated metabolism of other more toxic drugs, genetic deficiency of P450 enzymes, and medical illnesses such as liver and renal failure that will lead to further elevation of drug levels and delay in drug clearance, the likelihood of adverse events when multiple drugs are used in the elderly becomes truly dizzying. In consideration of the pharmacologic principles discussed, when prescribing drugs in the elderly, one might add to the often heard recommendation, "Start low and go slow," a third admonition, "Keep it as simple as possible!"

A double-blind randomised placebo-controlled study was conducted in healthy male volunteers to determine the effects of sertraline on the pharmacokinetics of diazepam and its primary metabolite, N-demethyldiazepam. The effect of sertraline on the plasma protein binding of diazepam was also studied. Sertraline 50 mg/day titrated over a 10-day period to 200 mg/day or placebo was administered for 32 days. A single intravenous dose of diazepam 10 mg was given before the start, and after 21 days of sertraline or placebo treatment. The pharmacokinetic analyses were based on data from 20 individuals. The systemic clearance of diazepam decreased by 32% (-0.100 ml/min/kg) in the sertraline group compared with a 19% decrease (-0.054 ml/min/kg) in the placebo group (p = 0.0266). However, this small difference (13%) between the 2 groups was not considered meaningful. Other than a prolonged time to maximum plasma concentration for N-demethyldiazepam, no other pharmacokinetic parameters were significantly altered by sertraline. The plasma protein binding of diazepam was unchanged by concomitant administration of sertraline. These results suggest that sertraline at the maximum recommended dosage under steady-state conditions, and demethylsertraline, the principal metabolite of sertraline, are unlikely to exert significant inhibitory effects on the CYP2C19 and CYP3A3/4 hepatic isoenzymes responsible for the metabolism of diazepam. Therefore, it would be expected that sertraline would, similarly, have a minimal effect on the pharmacokinetic profile of other drugs metabolised by these hepatic isoenzymes.

This paper presents an overview of the clinically relevant pharmacology of selective serotonin reuptake inhibitors (SSRIs) with an emphasis on their pharmacokinetics and effects on cytochrome P450 (CYP) enzymes. The SSRIs are potent inhibitors of the neuronal reuptake pump for serotonin (5-hydroxytryptamine; 5-HT) and have minimal effects on a number of other sites of actions (e.g. neuroreceptors and fast sodium channels). For this reason, drugs in this class have remarkable similarity as regards acute and maintenance antidepressant efficacy and tolerability profile. However, individual members of this class differ substantially in their pharmacokinetics and effects on CYP enzymes. Most SSRIs have a half-life (t1/2) of approximately 1 day. Fluoxetine, however, has a longer t1/2 of 2 to 4 days, and its active metabolite, norfluoxetine, has an extended t1/2 of 7 to 15 days. Fluoxetine, paroxetine and, to a lesser extent, fluvoxamine inhibit their own metabolism. That is not the case for citalopram or sertraline. There are nonlinear increases in paroxetine plasma concentrations with dosage increases, but proportional changes with citalopram and sertraline. Indirect data suggest that fluoxetine and fluvoxamine also have nonlinear pharmacokinetics over their usual dosage range. Age-related increases in plasma drug concentrations for citalopram (approximately 130%) and paroxetine (approximately 50 to 100%) have been observed in healthy elderly (65 to 75 years) persons versus those who are younger. There is an age-gender interaction for sertraline, with its plasma concentrations being 35 to 40% lower in young men than in elderly or young females or elderly males. While there is no apparent change in fluvoxamine plasma levels as a function of age, plasma drug concentrations are 40 to 50% lower in males than in females. Limited data from clinical trials suggest that age-related differences with fluoxetine may be comparable to those of citalopram and paroxetine. Marked differences exist between the SSRIs with regard to effects on specific CYP enzymes and, thus, the likelihood of clinically important pharmacokinetic drug-drug interactions. The most extensive in vitro and in vivo research has been done with fluoxetine, fluvoxamine and sertraline; there has been less with paroxetine and citalopram. The available in vivo data at each drug's usually effective antidepressant dose are summarised below. Citalopram produces mild inhibition of CYP2D6. Fluvoxamine produces inhibition (which would be expected to be clinically meaningful) of two CYP enzymes. CYP1A2 and CYP2C19, and probably a third, CYP3A3/4. Fluoxetine substantially inhibits CYP2D6 and probably CYP2C9/10, moderately inhibits CYP2C19 and mildly inhibits CYP3A3/4. Paroxetine substantially inhibits CYP2D6 but doses not appear to inhibit any other CYP enzyme. Sertraline produces mild inhibition of CYP2D6 but has little, if any, effect on CYP1A2, CYP2C9/10, CYP2C19 or CYP3A3/4. Understanding the similarities and differences in the pharmacology of SSRIs can aid the clinician in optimal use of this important class of antidepressants.

The effect of the selective serotonin reuptake inhibitor (SSRI) sertraline 200 mg/day on the metabolism of intravenously administered tolbutamide was examined in a randomised nonblinded parallel-group study in 25 healthy male volunteers. There was a small but statistically significant decrease (16%) in the clearance of tolbutamide in patients receiving the maximum recommended dosage of sertraline. The terminal elimination rate constant was also significantly reduced, corresponding to the increase in the terminal elimination half-life (from 6.9 to 8.6 hours). The decrease in clearance was not associated with any significant changes in plasma protein binding or in the apparent volume of distribution of tolbutamide. This suggests that the change in tolbutamide clearance may be due to a slight inhibition of the cytochrome P450 (CYP) isoenzyme CYP2C9/10 when sertraline was administered in its maximum recommended dosage. However, the small changes in the volume of distribution and plasma binding of tolbutamide after sertraline treatment indicate that there is a minimal interaction between sertraline and tolbutamide.

The number of antidepressants has expanded dramatically in the last decade as a result of the ability to design psychiatric medications in a rational manner. This paper provides a broad overview of these options while focusing on the most recently approved antidepressant, mirtazapine. The paper discusses the five major features that a physician needs to consider when selecting a medication for a patient: safety, tolerability, efficacy, payment, and simplicity. These five features are summarized by the mnemonic STEPS. The paper also proposes a pharmacologically based classificatory system that divides current antidepressants into eight groups based on the mechanism of action thought to underlie their antidepressant efficacy. Such a classificatory system can serve as an organizing principle for the practicing physician.

The in vivo effect of sertraline on oxidative drug metabolism mediated by cytochrome P450 (CYP) 3A was assessed by coadministration with alprazolam, carbamazepine, and terfenadine in three separate studies. Sertraline at doses of 50 to 200 mg/day for 10 to 20 days did not alter the pharmacokinetics of these CYP3A substrates/drugs.

The SSRIs have been used as an example to show how one might interpret the available evidence to draw conclusions about the relationships between drugs and P450s. Under what circumstances might one apply the knowledge of such relationships? First, the clinical implications must be considered when drugs with a narrow therapeutic index are coprescribed with other drugs that may affect P450s. For example, good clinical practice demands that before a TCA is coprescribed with another drug, the physician be aware of the potential for the second drug to interact with CYP2D6. Second, it may be helpful to consider P450 enzymes when adverse events occur during polypharmacy. It may happen that a known side effect of one drug occurs. Rather than attributing this to patient sensitivity, the physician should consider the possibility that a pharmacokinetic drug interaction increased plasma drug concentration, which in turn enhanced the probability of such an occurrence. Even when a pharmacokinetic drug interaction is considered as a possible cause, an appreciation of the role of P450s may lead to the realization that an interaction was not only possible but that it was likely. Finally, copharmacy can be used intentionally to produce controlled interactions. Indeed, planned pharmacokinetic drug interactions at the level of P450s have been proposed to reduce cyclosporine dosage requirements, to reduce variability of TCA levels, and to manipulate the contribution of alternative metabolic pathways to minimize toxic effects. As long as pharmaceuticals are metabolized by the P450 system, interactions with the various isozymes will be inescapable. It is fortunate that understanding them is becoming more tractable.