Sheldon H. Preskorn

An Innovative Design to Establish Proof of Concept of the Antidepressant Effects of the NR2B Subunit Selective N-Methyl-D-Aspartate Antagonist, CP-101,606, in Patients With Treatment-Refractory Major Depressive Disorder

This randomized, placebo-controlled, double-blind study was the first to evaluate the antidepressant efficacy, safety, and tolerability of an NR2B subunit-selective N-methyl-D-aspartate receptor antagonist, CP-101,606. Subjects had major depression, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and a history of treatment refractoriness to least 1 adequate trial of a selective serotonin reuptake inhibitor. The study had 2 treatment periods. In period 1, subjects first received a 6-week open-label trial of paroxetine and a single-blind, intravenous placebo infusion. Period 1 nonresponders (n = 30) then received a randomized double-blind single infusion of CP-101,606 or placebo plus continued treatment with paroxetine for up to an additional 4 weeks (period 2). Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale and 17-item Hamilton Depression Rating Scale. On the prespecified main outcome measure (change from baseline in the Montgomery-Åsberg Depression Rating Scale total score at day 5 of period 2), CP-101,606 produced a greater decrease than did placebo (mean difference, 8.6; 80% confidence interval, −12.3 to −4.5) (P < 0.10). Hamilton Depression Rating Scale response rate was 60% for CP-101,606 versus 20% for placebo. Seventy-eight percent of CP-101,606-treated responders maintained response status for at least 1 week after the infusion. CP-101,606 was safe, generally well tolerated, and capable of producing an antidepressant response without also producing a dissociative reaction. Antagonism of the NR2B subtype of the N-methyl-D-aspartate receptor may be a fruitful target for the development of a new antidepressant with more robust effects and a faster onset compared with those currently available and capable of working when existing antidepressants do not.

Clinically relevant pharmacology of selective serotonin reuptake inhibitors : An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism

SummaryThis 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 (t½) of approximately 1 day. Fluoxetine, however, has a longer t½ of 2 to 4 days, and its active metabolite, norfluoxetine, has an extended t½ 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 (≈130%) and paroxetine (≈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 does 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 anti-depressants.

Demonstration of the Efficacy and Safety of a Novel Substance P (NK1) Receptor Antagonist in Major Depression

The efficacy and safety of a selective NK1 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 (NK1) 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 NK1 antagonists (aprepitant and L-759274). NK1 antagonism is a replicated and generally well-tolerated antidepressant mechanism.

Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine

The pharmacokinetic interactions of sertraline and fluoxetine with the tricyclic antidepressant desipramine were studied in 18 healthy male volunteers phenotyped as extensive metabolizers of dextromethorphan. Concentrations in plasma were determined after 7 days of desipramine (50 mg/day) dosing alone, during the 21 days of desipramine and selective serotonin reuptake inhibitor (SSRI) coadministration (fluoxetine, 20 mg/day; sertraline, 50 mg/day), and for 21 days of continued desipramine administration after SSRI discontinuation. Desipramine Cmax was increased 4.0-fold versus 31% and AUC0-24 was increased 4.8-fold versus 23% for fluoxetine versus sertraline, respectively, relative to baseline after 3 weeks of coadministration. Desipramine trough concentrations approached baseline within 1 week of sertraline discontinuation but remained elevated for the 3-week follow-up period after fluoxetine discontinuation. Concentrations of SSRIs and their metabolites correlated significantly with desipramine concentration changes (for fluoxetine/norfluoxetine, r = 0.94 to 0.96; p < 0.001; for sertraline/desmethylsertraline, r = 0.63; p < 0.01). Thus, sertraline had less pharmacokinetic interaction with desipramine than did fluoxetine at their respective, minimum, usually effective doses.

Cytochrome P450 enzymes : Interpretation of their interactions with selective serotonin reuptake inhibitors. Part II.

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.

Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers.

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.

Brain concentrations of tricyclic antidepressants: single-dose kinetics and relationship to plasma concentrations in chronically dosed rats.

A previously reported method of measuring tricyclic antidepressant concentrations in brain tissue and plasma was used to measure amitriptyline (AMI) in rats following drug administration using different routes, doses, and time intervals. In rats given AMI intraperitoneally (IP), brain concentrations increased during the first 30 min after drug adminstration and then declined. Brain concentrations increased linearly with changes in IP dosage and increased logarithmically with changes in intravenous dosage. No simple relationship existed between brain and plasma concentrations in acutely dosed rats. However, a linear relationship existed between plasma and brain concentrations in chronically treated animals (r=0.96, P<0.001). The brain: plasma drug ratios observed in chronically treated rats corresponded to ratios reported in man. Thus, conclusions drawn from these studies can probably be extrapolated to the clinical situation. Based on our data, the molar concentration of drug achieved on therapeutic doses is 10-5–10-6 M. This information may aid in understanding the clinical relevance of in vitro drug: receptor binding studies which are typically reported in molar concentrations.

Central Nervous System Toxicity of Tricyclic Antidepressants: Phenomenology, Course, Risk Factors, and Role of Therapeutic Drug Monitoring

Central nervous system (CNS) toxicity of tricyclic antidepressants (TCAs) is serious, costly, frequent, and difficult to diagnose early in its course. We first reviewed all published, systematic population studies of such CNS toxicity. Of 976 TCA-treated patients, 58 (6%) developed TCA-induced CNS toxicity. The risk of this toxicity was positively correlated with TCA plasma levels. For levels greater than 450 ng/ml, the risk increased more than 10-fold (to 67%). We further analyzed 36 cases in terms of phenomenology, course, and potential risk factors of TCA-induced toxicity. A protean prodrome involving affective, psychotic, and cognitive symptoms preceded the delirium, which on average took 2 weeks to develop. The variability of this prodrome often leads to erroneous clinical decisions. Risk factors for delirium, in order of importance, included TCA concentration in plasma, age, and female gender.

Clinical and Demographic Factors Associated With DSM-IV Melancholic Depression

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.

Normalizing effects of EVP-6124, an α-7 nicotinic partial agonist, on event-related potentials and cognition: a proof of concept, randomized trial in patients with schizophrenia.

Cognitive impairment is a cause of significant disability in patients with schizophrenia. To date, no drug has been approved for this indication by the U.S. Food and Drug Administration. This article presents findings suggesting that a medication targeting the alpha-7 nicotinic acetylcholine receptor (&agr;7 nAChR) might meet this need. This single-center, randomized, parallel-group, double-blind,placebo-controlled study examined 21 medically stable patients with schizophrenia or schizoaffective disorder treated with second generation antipsychotics. Patients were treated with a daily dose of either 0.3 mg (n=8) or 1.0 mg (n=9) of EVP-6124, an &agr;7 nAChR partial agonist, or placebo (n=4). Treatment continued for 21 days while patients continued their usual antipsychotic medication: aripiprazole (10–30 mg/day), olanzapine (10–20 mg/day), paliperidone (3–12 mg/day), or risperidone (2–16 mg/day). Cognitive test performance, eventrelated electroencephalographic (EEG) potentials, clinical symptoms, laboratory values, and clinical side effects were measured. EVP-6124 was well tolerated and showed positive, and in some cases, dose-dependent effects on several EEG responses, especially the Mismatch Negativity and P300 potentials. Positive effects were also found in performance on cognitive tests that measured non-verbal learning, memory, and executive function. This study is an example of the type of early proof of concept trial that is done to enable drug developers to evaluate whether to continue research on an agent. Based on the promising findings in this study, larger phase II studies were initiated to further test the pro-cognitive effects of EVP-6124 in patients with chronic schizophrenia. Clinical Trials Registration: Safety, Tolerability, and Pharmacokinetic Study of EVP-6124 in Patients with Schizophrenia, NCT01556763 http://clinicaltrials.gov/ct2/show/NCT01556763?term=NCT01556763&rank=1 (Journal of Psychiatric Practice 2014;20:12–24)