A placebo-controlled comparison of the effects on sexual functioning of bupropion sustained release and fluoxetine.

BACKGROUND: Many antidepressants are associated with sexual dysfunction, a side effect that may lead to patients' dissatisfaction and noncompliance with treatment. OBJECTIVE: This study compared the efficacy, tolerability, and effects on sexual functioning of bupropion sustained release (bupropion SR) and the selective serotonin reuptake inhibitor fluoxetine. METHODS: In this multicenter, randomized, double-blind, double-dummy, parallel-group study, patients with recurrent major depression were treated with bupropion SR 150 to 400 mg/d, fluoxetine 20 to 60 mg/d, or placebo for up to 8 weeks. Depression and sexual-functioning status were assessed by site-specific trained investigators at weekly clinic visits; tolerability was assessed primarily by monitoring adverse events. RESULTS: Four hundred fifty-six patients participated in the study, 150 receiving bupropion SR, 154 fluoxetine, and 152 placebo. The majority of patients in each group completed the study (63% each, bupropion SR [n = 94] and fluoxetine [n = 97]; 67%, placebo [n = 102]). Bupropion SR and fluoxetine were similarly effective in the treatment of depressive symptoms. Beginning at week 2 and continuing throughout the study, significantly more fluoxetine-treated patients experienced orgasm dysfunction than did patients receiving bupropion SR or placebo (P < 0.001); similar results were seen in patients defined as clinical responders (> or =50% decrease from baseline in 21-item Hamilton Rating Scale for Depression [HAM-D] total score) (P < 0.001) and in those experiencing remission of depression (HAM-D total score <8) (P < 0.05). At various time points, worsened sexual functioning, sexual desire disorder, sexual arousal disorder, and dissatisfaction with sexual functioning in those satistied at baseline were more frequently associated with fluoxetine treatment than with bupropion SR or placebo. Both active treatments were well tolerated. CONCLUSIONS: Bupropion SR and fluoxetine were similarly effective and well tolerated in the treatment of depression. Fluoxetine, however, was more frequently associated with sexual dysfunction compared with bupropion SR. Bupropion SR may be an appropriate initial choice for the treatment of depression in patients concerned about sexual functioning.

Bupropion sustained release (SR) for the treatment of hypoactive sexual desire disorder (HSDD) in nondepressed women.

This article describes the results of the first report of bupropion sustained release (SR) in nondepressed females with hypoactive sexual desire disorder (HSDD). Eligible females entered a 4-week, single-blind, placebo baseline phase. Subjects, all of whom did not respond to placebo, continued in a single-blind active treatment phase where they received bupropion SR for up to 8 additional weeks. We assessed HSDD by using investigator ratings of sexual desire and sexual functioning. Of the 51 evaluable subjects who entered the active treatment phase, 29% responded to treatment with bupropion SR. Bupropion SR was generally well tolerated. Pending the results of further study, bupropion SR may offer a treatment option for women with HSDD.

Response in relation to baseline anxiety levels in major depressive disorder treated with bupropion sustained release or sertraline.

Our objective was to determine if pretreatment anxiety levels were associated with preferential response to bupropion sustained release (n = 122) or sertraline (n = 126) during a 16-week randomized acute phase treatment study. Both agents had comparable antidepressant activity, and comparable anxiolytic effects using the intent-to-treat sample. Baseline anxiety levels were not related to antidepressant efficacy, and they did not differentiate responders to each agent. Time to clinically significant anxiolysis did not differentiate between treatment groups or between responders to each agent. These results contradict the commonly held, but unsubstantiated, belief that in clinically depressed anxious patients, serotonergic antidepressants are especially anxiolytic and that such patients preferentially benefit from the antidepressant or anxiolytic effects of selective serotonin reuptake inhibitors. Thus, the clinical decision to select between these two agents when treating depressed outpatients cannot rest on either levels of pretreatment anxiety or on anticipation of more rapid or more complete anxiolysis.

Do bupropion SR and sertraline differ in their effects on anxiety in depressed patients?

OBJECTIVE: To examine the effects of bupropion sustained release (SR) and sertraline on anxiety in outpatients with recurrent DSM-IV-defined major depressive disorder. METHOD: This retrospective analysis was conducted using pooled data from 2 identical, 8-week, acute-phase, double-blind, placebo-controlled, parallel-group studies of bupropion SR (N = 234), sertraline (N = 225), and placebo (N = 233). Symptoms of anxiety and depression were measured using the 14-item Hamilton Rating Scale for Anxiety (HAM-A) and the 21-item Hamilton Rating Scale for Depression (HAM-D-21), respectively. Percentage reduction in baseline HAM-A total score for each treatment week was calculated to determine whether the time to onset of anxiolytic activity differed among antidepressant responders to each agent. Central nervous system (CNS) adverse events were tabulated. RESULTS: Bupropion SR and sertraline were comparably effective, both were superior to placebo in reducing depressive symptoms. and they did not differ in their effect on anxiety symptoms. Antidepressant responders (> 50% reduction in baseline HAM-D-21 score) in both groups showed marked and comparable reductions in HAM-A scores (baseline to exit). There were no differences between bupropion SR and sertraline in the median time (4 weeks) to reach a clinically significant anxiolytic effect (> or = 50% reduction in baseline HAM-A score). CNS adverse events were comparable for bupropion SR and sertraline, except for somnolence, which was more common in sertraline-treated patients. CONCLUSION: Bupropion SR and sertraline had comparable antidepressant and anxiolytic effects and an equally rapid onset of clinically significant anxiolytic activity. There was no difference in the activating effects between the 2 antidepressants. Selection between these 2 agents cannot be based on either anticipation of differential anxiolytic activity or differential CNS side effect profiles.

Naratriptan efficacy in migraineurs who respond poorly to oral sumatriptan.

OBJECTIVES: To determine whether 347 patients would respond to a 50-mg oral dose of sumatriptan, even though they considered themselves poor responders to this acute therapy for migraine, and to investigate whether oral naratriptan can be an effective acute therapy for migraine in the subset of patients who did not respond to sumatriptan under double-blind, well-controlled conditions. BACKGROUND: Although most migraineurs respond to sumatriptan, there remains a need for an effective alternative for those who do not respond. Naratriptan is a more potent and more lipophilic member of this class of agent and could prove beneficial in such patients. This is the first well-controlled study to assess the value of another 5-HT1B/1D agonist in this difficult patient subset. METHODS: This study comprised two migraine attacks. The first (attack 1) was a single-blind assessment of the efficacy of sumatriptan (50 mg orally) in patients with a history of poor response to the drug. The second (attack 2) was a randomized, parallel group, double-blind, placebo-controlled trial of naratriptan (2.5 mg orally) in nonresponders to oral sumatriptan. RESULTS: Attack 1: About two thirds of this selected migraine population did not respond to sumatriptan. Attack 2: Naratriptan was statistically superior to placebo for headache relief at 2 hours and 4 hours, as well as for most other features of migraine attacks. These data suggest an intrinsic efficacy of naratriptan in this patient subset and not a coincidental response. No unexpected tolerability issues arose. CONCLUSIONS: Naratriptan is an alternative therapy for migraineurs who respond poorly to oral sumatriptan. No response to one "triptan" does not necessarily predict no response to them all.

Migraine polypharmacy and the tolerability of sumatriptan: a large-scale, prospective study.

Polypharmacy (the prescription of more than one therapy for a single patient) and subcutaneous (s.c.) sumatriptan tolerability were prospectively studied in 12,339 migraineurs, each followed for up to 1 year. Inclusion/exclusion criteria were minimal and mirrored United States Imitrex labeling. Drug usage and compliance monitoring were automatically interfaced with prescription refill. Concomitant drugs were used by 79% of patients, with analgesics, antidepressants, and sedatives used most commonly. No adverse interactions between sumatriptan and neurological drugs were found, possibly reflecting relative inability of the former to cross the blood-brain barrier. No difference in cardiovascular adverse events was associated with oral contraceptive use, which was more common than expected. No other drug class influenced adverse event probability, although sample sizes for these comparisons was sometimes <400 patients. This study confirms the prevalence of polypharmacy in migraine, identifies the drugs used, and concludes that, on a population basis, the tolerability of s.c. sumatriptan, when used according to labeled instructions, is unaffected by these concomitant drugs.

The efficacy of lamotrigine in rapid cycling and non-rapid cycling patients with bipolar disorder.

BACKGROUND: Patients with bipolar disorder (BD) who have rapid cycling features are often treatment refractory. Clear and conclusive evidence regarding effective treatments for this group is not available. METHODS: Patients with diagnoses of refractory bipolar disorder who were currently experiencing manic, mixed, depressive, or hypomanic episodes were treated with lamotrigine as add-on therapy (60 patients) or monotherapy (15 patients). We compared the efficacy of lamotrigine in the 41 rapid cycling and 34 non-rapid cycling patients with BD. RESULTS: Improvement from baseline to last visit was significant among both rapid cycling and non-rapid cycling patients for both depressive and manic symptomatology. For patients entering the study in a depressive episode, improvement in depressive symptomatology was equivalent in the two groups. Among patients entering the study in a manic, mixed, or hypomanic episode, those with rapid cycling improved less in manic symptomatology than did non-rapid cycling patients. Among rapid cycling patients with initial mild-to-moderate manic symptom severity, improvement was comparable to that in non-rapid cycling subjects; however, the subset of rapid cycling patients with severe initial manic symptomatology had little improvement in mania. Rapid cycling patients had earlier onset and more lifetime episodes of mania, depression, and mixed mania. CONCLUSIONS: Lamotrigine was generally effective and well tolerated in this group of previously non-responsive, rapid cycling bipolar patients.

Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder.

OBJECTIVE: New mood stabilizers are needed that possess efficacy for all phases of bipolar disorder. This study was designed to provide preliminary evidence for the safety and efficacy of a new anticonvulsant, lamotrigine, in adult patients with bipolar disorder who had been inadequately responsive to or intolerant of prior pharmacotherapy. METHOD: A 48-week, open-label, prospective trial was conducted in 75 patients with bipolar I or bipolar II disorder. Lamotrigine was used as adjunctive therapy (N = 60) or monotherapy (N = 15) in patients presenting in depressed, hypomanic, manic, or mixed states. RESULTS: Of the 40 depressed patients included in the efficacy analysis, 48% exhibited a marked response and 20% a moderate response as measured by reductions in 17-item Hamilton Depression Rating Scale scores. Of the 31 with a hypomanic, manic, or mixed state, 81% displayed a marked response and 3% a moderate response on the Mania Rating Scale. From baseline to endpoint, the depressed patients exhibited a 42% decrease in Hamilton depression scale scores, and the patients presenting with hypomania, mania, or a mixed state exhibited a 74% decrease in Mania Rating Scale scores. The most common drug-related adverse events were dizziness, tremor, somnolence, headache, nausea, and rash. Rash was the most common adverse event resulting in drug discontinuation (9% of patients); one patient developed a serious rash and required hospitalization. CONCLUSIONS: These open-label data provide preliminary evidence that lamotrigine may be an effective treatment option for patients with refractory bipolar disorder; however, potential benefits must be weighed against potential side effects, including rash.

Regulation of neurotensin receptor mRNA expression by the receptor antagonist SR 48692 in the rat midbrain dopaminergic neurons.

In this study, we demonstrated that the tyrosine hydroxylase-like immuno-reactive (possibly dopaminergic) neurons express neurotensin receptor mRNA in the rat substantia nigra and in the ventral tegmental area. Additionally, 2 weeks treatment with the neurotensin receptor antagonist SR 48692 increased mRNA levels in the substantia nigra. These data suggest that neurotensin receptor expression in the perikarya and in the terminal regions of dopaminergic neurons is regulated by its endogenous agonist in vivo.

Haloperidol but not clozapine increases neurotensin receptor mRNA levels in rat substantia nigra.

We examined the effects of chronic (2 weeks) treatment with a typical neuroleptic, haloperidol (1 mg/kg, s.c.), and an atypical neuroleptic, clozapine (20 mg/kg, s.c.), on neurotensin receptor (NTR) mRNA levels by in situ hybridization histochemistry. Quantitative OD analysis showed haloperidol-induced NTR mRNA levels in the substantia nigra/ventral tegmental area (SN/VTA) 110% over control levels (significant difference from the control, p < 0.05). In contrast, the same analysis applied to the sections from clozapine-treated animals showed no significant change in NTR mRNA levels compared with matched control sections (p > 0.05). Thus, chronic treatment with haloperidol but not clozapine resulted in elevated levels of NTR mRNA within the SN/VTA. These results suggest that the high incidence of extrapyramidal side effects of typical neuroleptics could result from changes in NTR expression in the SN/VTA.

Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics.

Based on molecular cloning studies, five different muscarinic receptor subtypes exist: m1, m2, m3, m4, and m5. We determined the affinity and selectivity of binding for sixteen antidepressants, two of their metabolites, and three antihistaminics (H1) at these subtypes. Using Chinese hamster ovary cells (CHO-K1) transfected with genes for the human muscarinic receptor subtypes, we obtained equilibrium dissociation constants (Kds) from competitive radioligand binding studies with [3H]-quinuclidinyl benzilate ([3H]QNB) and membranal preparations of these cells. QNB was the most potent compound studied (Kd 30-80 pM). Mequitazine (Kd 6-14 nM) and amitriptyline (Kd 7-16 nM) exhibited the highest affinity among the antihistaminics and antidepressants, respectively. Among the antidepressants examined were the serotonin-selective drugs sertraline and fluoxetine, both of which displayed Kd values > 1 microM. The remaining antidepressants were moderate to weak antagonists with some eliciting no radioligand competition at high concentrations. The compounds studied showed no significant selectivity among the five cloned subtypes.

Blockade by newly-developed antidepressants of biogenic amine uptake into rat brain synaptosomes.

We determined the uptake blockade produced by eight new antidepressant drugs (etoperidone, femoxetine, lofepramine, nefazodone, paroxetine, sertraline, tomoxetine, and venlafaxine), two metabolites of newer antidepressants (desmethylsertraline and norfluoxetine), seven previously reported antidepressants, and carbamazepine. Inhibitor constants (Kis) for uptake blockade were obtained from competitive uptake studies with [3H]norepinephrine, [3H]5-hydroxytryptamine, and [3H]dopamine in rat brain synaptosomes prepared from hippocampus, frontal cortex, and striatum, respectively. Among the newer compounds, tomoxetine (Ki = 0.7 nM) and lofepramine (Ki = 1.9 nM) were potent and selective [3H]norepinephrine uptake blockers; paroxetine (Ki = 0.73 nM), sertraline (Ki = 3.4 nM), and femoxetine (Ki = 22 nM) potently and selectively inhibited [3H]5-hydroxytryptamine uptake. Although none of the drugs was potent for [3H]dopamine uptake blockade, sertraline was the most potent (Ki = 260 nM). These data are useful in predicting adverse effects and drug-drug interactions of antidepressants.

The rat neurotensin receptor expressed in Chinese hamster ovary cells mediates the release of inositol phosphates.

To study second messenger synthesis mediated by the cloned rat neurotensin receptor, we derived a cell line stably expressing this receptor. The cDNA clone of this receptor was subcloned into the pcDNA1neo expression vector. This construct was then used to transfect Chinese hamster ovary (CHO)-K1 cells. Colony clones, selected for resistance to antibiotic G-418 sulfate, were isolated and grown separately. Nineteen individual clones were screened for total [3H]neurotensin binding as an indication of neurotensin receptor expression. The clone (CHO-rNTR-10) showing the highest level of specific [3H]neurotensin binding was characterized further. With intact cells, the equilibrium dissociation constant (KD) for specific [3H]neurotensin binding was 18 nM, and the maximal number of binding sites (Bmax) was 900 fmol/mg of protein or 740 fmol/10(6) cells (approximately 4.4 x 10(5) sites on the cellular surface). Whereas the KD was similar to that found in other cellular systems, for example, the murine neuroblastoma clone N1E-115, the Bmax exceeded previously reported values. Incubation of intact CHO-rNTR-10 cells with neurotensin caused the release of inositol phosphates in a dose-dependent manner (EC50 = 3 nM), results indicating that the expressed transfected receptor was functional. Neurotensin did not inhibit cyclic AMP levels stimulated by forskolin. As with other systems, neurotensin (8-13) was more potent than neurotensin Neurotensin-mediated inositol phosphate release is the first report of second messenger synthesis for this receptor expressed in a transfected cell line. These results suggest that the relation between structure and function of the neurotensin receptor can be readily studied in transfected cell lines.