Kimberly A. Yonkers

Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder

BACKGROUND Sleep disturbances are common in major depressive disorder. In previous open-label trials, nefazodone improved sleep continuity and increased rapid eye movement (REM) sleep, while not affecting stage 3/4 sleep or REM latency: in contrast, fluoxetine suppressed REM sleep. This study compared the objective and subjective effects of nefazodone and fluoxetine on sleep. METHODS This paper reports combined results of three identical, multisite, randomized, double-blind, 8-week, acute-phase trials comparing nefazodone (n = 64) with fluoxetine (n = 61) in outpatients with nonpsychotic major depressive disorder and insomnia. Sleep electroencephalographic (EEG) recordings were gathered at baseline and weeks 2, 4, and 8. Clinical ratings were obtained at weeks 1-4, 6, and 8. RESULTS Nefazodone and fluoxetine were equally effective in reducing depressive symptoms; however, nefazodone differentially and progressively increased (while fluoxetine reduced) sleep efficiency and reduced (while fluoxetine increased) the number of awakenings in a linear fashion over the 8-week trial. Fluoxetine, but not nefazodone, prolonged REM latency and suppressed REM sleep. Nefazodone significantly increased total REM sleep time. Clinical evaluations of sleep quality were significantly improved with nefazodone compared with fluoxetine. CONCLUSIONS Nefazodone and fluoxetine were equally effective antidepressants. Nefazodone was associated with normal objective, and clinician- and patient-rated assessments of sleep when compared with fluoxetine. These differential sleep EEG effects are consistent with the notion that nefazodone and fluoxetine may have somewhat different modes and spectra of action.

Venlafaxine in the treatment of premenstrual dysphoric disorder.

OBJECTIVE To evaluate the efficacy and safety of venlafaxine, a new‐generation antidepressant that selectively inhibits serotonin and norepinephrine reuptake, in the treatment of premenstrual dysphoric disorder (PMDD). METHOD We conducted a randomized, double‐blind, placebo‐controlled, parallel‐group, flexible‐dose trial. After three screening cycles, including a single‐blind placebo cycle, 164 women were randomly assigned to double‐blind treatment with venlafaxine (50–200 mg/day) or placebo for four menstrual cycles. Primary outcome measures were the total premenstrual symptom scores as assessed by a daily symptom report (DSR) and the Hamilton Rating Scale for Depression. RESULTS Venlafaxine was significantly more effective than placebo in reducing PMDD symptoms as assessed by DSR scores (P < .001 for last observation carried forward and observed analyses). Sixty percent of venlafaxine versus 35% of placebo subjects improved >50% (P = .003). Forty‐three percent of venlafaxine subjects versus 25% of placebo subjects experienced symptom remission, defined as reduction of DSR scores to the postmenstrual level (P = .034). Venlafaxine treatment was significantly better than placebo for all statistically derived DSR factors (mood, function, pain, and physical symptoms). Improvement was relatively swift, with approximately 80% symptom reduction in the first treatment cycle. Mean venlafaxine doses ranged from 50 mg/day in the first treatment cycle to 130 mg/day in the fourth treatment cycle. Adverse events such as nausea, insomnia, and dizziness were mild and transient. CONCLUSIONS Venlafaxine is significantly more efficacious than placebo for PMDD treatment. Response to treatment can occur in the first treatment cycle, and venlafaxine is well tolerated. Further studies are needed to evaluate the potential of intermittent (luteal phase) dosing for this cyclic disorder and the efficacy of long‐term maintenance treatment with venlafaxine.

A multicenter, double-blind comparison of the effects of nefazodone and fluoxetine on sleep architecture and quality of sleep in depressed outpatients

This study was an 8-week, randomized, double-blind, parallel-group investigation that compared the effects of nefazodone and fluoxetine on sleep architecture and on clinician- and patient-rated sleep measures in 43 outpatients with moderate to severe, nonpsychotic major depressive disorder and insomnia. Twenty-two patients received nefazodone 200 mg daily for 1 week, followed by 400 mg daily for 7 weeks. Twenty-one patients received fluoxetine 20 mg daily. Dosage increases (to 500 mg/day for nefazodone and 40 mg/day for fluoxetine) were available after day 29, depending on clinician judgement. Sleep parameters were measured during baseline phase, while patients were unmeasured and symptomatic, and at weeks 2, 4, and 8 of treatment. Nefazodone and fluoxetine were equally effective as antidepressants. However, compared with baseline, nefazodone increased sleep efficiency and reduced the number of awakenings and percent awake and movement time, whereas fluoxetine increased the number of awakenings and did not significantly alter sleep efficiency or percent awake and movement time. Although fluoxetine increased stage 1 sleep and rapid eye movement (REM) latency and reduced total percent REM sleep, nefazodone increased REM sleep, decreased REM latency, and did not alter stage 1 sleep. Differences between treatment groups, based on change from baseline, revealed greater sleep efficiency, fewer awakenings, less percent awake and movement time, less percent stage 1 and more REM sleep, and shorter REM latency for nefazodone compared with fluoxetine. Significantly greater improvement in clinician- and patient-rated sleep disturbance was found with nefazodone compared with fluoxetine. Nefazodone was associated with better sleep quality.

Paroxetine as a treatment for premenstrual dysphoric disorder.

Research into the psychobiology of premenstrual dysphoric disorder (PDD) finds alterations in markers associated with serotonergic neurotransmission.Supporting this is work showing that patients with PDD respond to some agents that block the reuptake of serotonin. In this open trial, patients were t

Recognition of depression in obstetric/gynecology practices

Depression is a common and serious health problem that occurs twice as often in women as in men. The lifetime prevalence of major depression in women is estimated to be as high as 21%. Although less severe and less common, mild depression and dysthymia (chronic mild depression) can cause functional disability and require treatment. Regardless of severity or duration, depression can be difficult to recognize because it frequently is masked by complaints that accompany other common obstetric and gynecologic illnesses and events. This article reviews the various depressive disorders in women with a focus on presentations that occur in obstetric and gynecologic practice.

Adrenergic receptors in premenstrual dysphoric disorder: I. Platelet α2 receptors: Gi protein coupling, phase of menstrual cycle, and prediction of luteal phase symptom severity

BACKGROUND Abnormal alpha 2-adrenergic receptor (AR) function is implicated in anxiety and depressive disorders. Premenstrual dysphoric disorder (PMDD) is characterized by anxiety and depressive symptoms, which may be associated with changes in alpha 2AR function. Previous studies on alpha 2AR function during phases of the menstrual cycle in controls and PMDD patients are inconsistent. METHODS alpha 2AR function was examined in 16 PMDD patients and 15 controls during the follicular phase, and in 10 PMDD patients during late luteal phase. Antagonist-measured maximum binding capacity, agonist-measured receptor density in high- and low-conformational states, and agonist affinity to both states were measured. Coupling efficiency to Gi protein was estimated. RESULTS There were no significant differences in coupling efficiency. PMDD patients had significantly low antagonist affinity; there were no differences in other binding parameters. There were no changes in alpha 2AR binding parameters between phases of menstrual cycle in PMDD women. alpha 2AR density and symptom severity were inversely related during the follicular phase in controls and patients. During luteal phase, alpha 2AR density correlated positively with symptom severity in patients. High follicular alpha 2AR density predicted more severe luteal symptoms in PMDD patients. CONCLUSIONS These findings are discussed in view of the molecular biology of alpha 2AR, and their role in PMDD, anxiety, and depressive disorders.

Adrenergic receptors in premenstrual dysphoric disorder. II. Neutrophil β2-adrenergic receptors: Gs protein coupling, phase of menstrual cycle and prediction of luteal phase symptom severity

Abnormal beta2-adrenergic receptor coupling to Gs protein is implicated in depressive disorders. Steroid hormones and antidepressants modulate beta-adrenergic receptor coupling, which may relate to the therapeutic efficacy of antidepressants. We examined beta2-adrenergic receptors in 18 patients with premenstrual dysphoric disorder (PMDD), in 15 control subjects during the follicular phase and in 12 patients during late luteal phase. Antagonist-measured receptor density, agonist-measured receptor density in the high- and low-conformational states and agonist affinity to both states were measured. Coupling indices to Gs protein were determined from agonist-displacement experiments. Follicular beta2-adrenergic receptor density was higher in patients than in control subjects, with a trend for higher receptor density in the high-conformational state. The phase of menstrual cycle had no effect on beta2-adrenergic receptor regulation in PMDD. Exploratory correlations showed that the K(L)/K(H) ratio was related to anxiety ratings in control subjects and %R(H) was correlated with symptom severity in patients. In patients, follicular beta2-adrenergic receptor binding measures were correlated with luteal symptom severity. These findings suggest abnormal beta2-adrenergic receptor regulation in PMDD. Further exploration of the role of beta-adrenergic receptor kinase, sex steroid hormones and antidepressants on beta-adrenergic receptor regulation in PMDD is warranted.

Lithium During Pregnancy Drug Effects and Their Therapeutic Implications

SummaryLithium is used as a primary treatment or augmentation therapy for several psychiatric conditions, such as bipolar depression, mania and unipolar depression. For many patients with bipolar disorder, it is the most effective mood stabiliser.More than half of the patients maintained on lithium are women, and many are of reproductive age. An unknown proportion of women who are receiving lithium maintenance therapy become pregnant, posing numerous clinical issues for the obstetrician, psychiatrist and patient. The specific problems associated with lithium exposure vary during different stages of gestation. The risk of the serious heart defect, Ebstein’s anomaly, exists if the drug is taken during weeks 2 to 6 post-conception; risks of fetal/neonatal complications occur if lithium is taken during the second and third trimesters.Given the effects of lithium on the conceptus, potentially safer alternatives may be required. The best case scenario is to counsel fecund women who require lithium to plan pregnancy, allowing for a temporary change in treatment regimen during the period of embryogenesis. If lithium therapy is reinstituted during the second and third trimesters, fetal monitoring for altered renal and endocrine function is important. Lithium requirements usually increase in the third trimester, but should be decreased in the peripartum period to avoid drug toxicity in the neonate and mother. Ultimately, the risk/benefit considerations must guide clinicians and patients in the decision to use lithium during pregnancy.

Diagnosis and treatment of premenstrual dysphoric disorder

Premenstrual syndrome (PMS) is a common problem and patients with PMS are encountered by obstetricians, gynecologists, family practitioners, internists (general physicians) and psychiatrists. Despite several decades of biological research, the etiology of the disorder is still elusive. The introduction of a psychiatric category called premenstrual dysphoric disorder (PMDD), describing women with severe emotional premenstrual symptoms, has advanced biological treatment research by identifying a more homogeneous patient population. This paper aims to review our current understanding of the clinical presentation, underlying psycho-biology, and essentials of treatment for premenstrual dysphoric disorder.

Paroxetine for the treatment of premenstrual dysphoric disorder

Research into the psychobiology of premenstrual dysphoric disorder (PDD) finds alterations in markers associated with serotonergic neurotransmission. Supporting this is work showing that patients with PDD respond to some agents that block the reuptake of serotonin. In this open trial, patients were treated for one cycle with placebo and then for three consecutive cycles with the serotonin reuptake inhibitor paroxetine. The study population was composed of 14 participants who met DSM-IV criteria for PDD with moderate to severe symptomatology and specifically endorsed anger and irritability as a central premenstrual complaint. Patients showed modest improvement over the course of the pretreatment evaluation, with significant improvement occurring for feelings of worthlessness, decreased interest, and low energy. The effects of active treatment were marked by the first active cycle with luteal phase 17-item Hamilton Rating Scale for Depression scores decreasing from 14.9 (+/- 5.3) to 8.2 (+/- 4.9) in the first, 7.8 (+/- 5.1) in the second, and 7.8 (+/- 6.8) in the third active treatment cycles (F[1,13] = 17.6; p < 0.0001). A group of items from daily ratings indicative of anger and irritability (mood swings, anger and irritability, behavioral dyscontrol, and interpersonal conflicts) also showed improvement (F[1,13] = 5.94; p < 0.03). Various definitions of response were applied to treatment completers. The most conservative measure, the Clinical Global Impression (CGI), revealed that 7 of 14 patients had a complete response (CGI = 1 or 2) whereas 4 patients had a partial response (CGI = 3). These open trial findings are consistent with the notion that paroxetine is effective in the acute phase for the treatment of PDD.