Open-label sildenafil treatment of partial and non-responders to double-blind treatment in men with antidepressant-associated sexual dysfunction.

Fifty partial and non-responders (Clinical Global Impression-Sexual Function (CGI-SF) score>2), out of 76 men who completed a 6-week, double-blind, placebo-controlled trial of sildenafil treatment for serotonergic antidepressant-associated sexual dysfunction, were eligible for an additional 6-week trial of open-label sildenafil (50 mg adjustable to 100 mg) under the same protocol, with blind maintained to initial assignment. Participation (double-blind and open-label) required major depressive disorder in remission (MDD-R) and continuing antidepressant medication. Forty-three entered open-label study: 16/17 initially randomized to sildenafil (sildenafil/sildenafil) and 27/33 initially randomized to placebo (placebo/sildenafil). Thirty-five of 43 (81%) achieved full response (CGI-SF

Randomized dose-ranging pilot trial of omega-3 fatty acids for postpartum depression.

OBJECTIVE: Postpartum depression (PPD) affects 10-15% of mothers. Omega-3 fatty acids are an intriguing potential treatment for PPD. METHOD: The efficacy of omega-3 fatty acids for PPD was assessed in an 8-week dose-ranging trial. Subjects were randomized to 0.5 g/day (n = 6), 1.4 g/day (n = 3), or 2.8 g/day (n = 7). RESULTS: Across groups, pretreatment Edinburgh Postnatal Depression Scale (EPDS) and Hamilton Rating Scale for Depression (HRSD) mean scores were 18.1 and 19.1 respectively; post-treatment mean scores were 9.3 and 10.0. Percent decreases on the EPDS and HRSD were 51.5% and 48.8%, respectively; changes from baseline were significant within each group and when combining groups. Groups did not significantly differ in pre- or post-test scores, or change in scores. The treatment was well tolerated. CONCLUSION: This study was limited by small sample size and lack of placebo group. However, these results support further study of omega-3 fatty acids as a treatment for PPD.

Bipolar disorder in women: reproductive events and treatment considerations.

OBJECTIVE: Bipolar disorders are prevalent in women. Women with bipolar disorder often present with different clinical features than men. Reproductive events and hormonal treatments may impact the course of bipolar disorder. Our main objectives are to i) assess the impact of reproductive events on the course of the disorder, and ii) to discuss the relationships between reproductive events and psychiatric treatments. METHOD: A literature search was conducted of MEDLINE journals from 1965 to present. Manual literature searches were also conducted. We review the presentation, clinical course, and treatment considerations of bipolar disorder in women, with emphasis on treatment considerations in the context of reproductive events. Treatment-related issues such as teratogenicity, breastfeeding, polycystic ovarian syndrome, weight gain and obesity, and medication interactions with oral contraceptives are reviewed. RESULTS: Women with bipolar disorder may be more vulnerable to mood episodes in the context of reproductive events, particularly postpartum. In women of reproductive age, mood stabilizers must be selected with teratogenic risks in mind, with the highest reported risks in pregnancy with valproate, and the greatest concern during breastfeeding with lithium use. In the areas of the perimenopause and polycycstic ovarian syndrome, more data are needed to advise treatment decisions. CONCLUSION: We urgently need further study in these areas to deliver care that is appropriate to women with bipolar disorder.

Sertraline versus imipramine to prevent relapse in chronic depression.

BACKGROUND: Chronic depressions are common, disabling and under-treated, and long-term treatment is little studied. We report the continuation phase results from a long-term treatment study. METHODS: After 12 weeks of acute phase treatment in a double-blind, randomized, parallel-group, multi-center trial of sertraline or imipramine, patients with chronic depression (> or = 2 years in major depression, or major depression superimposed on dysthymia) continued study drug for 16 weeks. Initially, 635 patients were randomized to sertraline or imipramine in a 2:1 ratio. Nonresponders after 12 weeks entered a 12-week double-blind crossover trial of the alternate medication. Entry into continuation treatment required at least a satisfactory response (partial remission) to initial or crossover treatment. RESULTS: Of 239 acute or crossover responders to sertraline, 60% entered continuation in full remission and 40% with a partial remission. These proportions were identical for imipramine patients (n = 147). For both drug groups, over two-thirds of those entering in full remission retained it. For those entering in partial remission, over 40% achieved full remission. Patients requiring crossover treatment were less likely to maintain or improve their response during continuation treatment. The two drugs did not differ significantly in response distribution, drop out rates or discontinuation due to side effects during continuation treatment. LIMITATIONS: The absence of a placebo group constrains interpretation of our results, but chronic depressions have low placebo response rates. CONCLUSIONS: Most chronic depression patients who remit with 12 weeks of sertraline or imipramine treatment maintain remission during 16 weeks of continuation treatment. Most patients with a satisfactory therapeutic response (partial remission) after 12 weeks of treatment maintain it or further improve. Patients treated with imipramine experienced more side effects, but both drugs were well tolerated.

Citalopram as adjunctive therapy in bipolar depression.

BACKGROUND: The treatment of bipolar depression remains a major clinical challenge. The effectiveness and safety of adjunctive citalopram were evaluated in DSM-IV-diagnosed bipolar depressed patients in a 5-site study. METHOD: The treatment strategy consisted of an open-label add-on design in which patients received 8 weeks of acute treatment with citalopram adjunctive to their ongoing treatment with mood stabilizers. Ongoing treatment with 1 antipsychotic, 1 anxiolytic, and 1 hypnotic agent was permitted. Responders to the 8-week trial then received 16 weeks of additional treatment with citalopram. RESULTS: Forty-five subjects entered the trial; 12 dropped out before the end of the acute treatment phase. Of the 33 patients who completed the acute treatment phase, 64% (N = 21) were responders and 36% (N = 12) were nonresponders. In the continuation phase of the study, 14 patients achieved sustained remission, 3 patients did not achieve remission before completing 16 weeks of continuation treatment, 2 patients experienced a relapse, and 2 patients dropped out of the study and did not have a chance to remit. In spite of the extensive concomitant medication usage allowed in this study, citalopram treatment was well tolerated and the level of reported adverse events (including headache, nausea, diarrhea, and sexual dysfunction) relatively low. CONCLUSION: The high response rate, the high rate of sustained remission, and the low rate of adverse events strongly support the use of citalopram as a treatment for bipolar I or II depression. These findings should stimulate a controlled double-blind trial to demonstrate even more clearly the usefulness of this drug in the therapeutic regimen for bipolar disorder.

Risk-benefit decision making for treatment of depression during pregnancy.

OBJECTIVE: The Committee on Research on Psychiatric Treatments of the American Psychiatric Association identified treatment of major depression during pregnancy as a priority area for improvement in clinical management. The goal of this article was to assist physicians in optimizing treatment plans for childbearing women. METHOD: The authors' work group developed a decision-making model designed to structure the information delivered to pregnant women in the context of the risk-benefit discussion. Perspectives of forensic and decision-making experts were incorporated. RESULTS: The model directs the psychiatrist to structure the problem through diagnostic formulation and identification of treatment options for depression. Reproductive toxicity in five domains (intrauterine fetal death, physical malformations, growth impairment, behavioral teratogenicity, and neonatal toxicity) is reviewed for the potential somatic treatments. The illness (depression) also is characterized by symptoms of somatic dysregulation that compromise health during pregnancy. The patient actively participates and provides her evaluation of the acceptability of the various treatments and outcomes. Her capacity to participate in this process provides evidence of competence to consent. Included in the decision-making process are the patient's significant others and obstetrical physician. The process is ongoing, with the need for incorporation of additional data as the pregnancy and treatment response progress. CONCLUSIONS: The conceptual model provides structure to a process that is frequently stressful for both patients and psychiatrists. By applying the model, clinicians will ensure that critical aspects of the risk-benefit discussion are included in their care of pregnant women.

Sexual side effects of antidepressant drugs.

Sexual functioning often suffers during depression, although depressed people continue to value sex. Many popular antidepressants further impair sexual functioning, with highly serotonergic agents affecting orgasm and libido prominently. This paper addresses clinical assessment of sexual side effects from antidepressant drugs and reviews treatment strategies, including purported antidotes. We pay particular attention to sildenafil, on which there are impressive data and ongoing controlled studies.

How fast are antidepressants?

BACKGROUND: For years, investigators have tried to determine the speed of onset of antidepressant drugs. Claims that particular drugs may produce a faster response in patients than other agents have been made, but such claims have never been confirmed. METHOD: The authors reviewed reports from studies of the speed of onset of antidepressant therapies and other studies that revealed information on this topic. We compiled a list of factors that can affect the results of such studies and interpretations of study results. In addition, we reviewed literature concerned with methods of speeding up antidepressant responses. RESULTS: No antidepressant medication currently available has been shown conclusively to have a more rapid onset of action than any other. However, some methods of augmentation may have the potential to speed responses. Somatic therapies such as electroconvulsive therapy, phototherapy, and therapeutic sleep deprivation may be the fastest options available at this time. CONCLUSION: All available antidepressant medications are usually taken for several weeks before future responders will display a significant therapeutic benefit. If a patient does not show at least a 20% improvement within the first 2 to 4 weeks of treatment, the treatment regimen should be altered. For patients who do show early benefits from a medication trial, one can expect additional benefits to accrue over an 8- to 12-week period and to improve overall outcome compared with those slower to respond. Future trials need to address methodological confounds, but a truly "faster antidepressant" will probably require new neuroscience technology.

Gender differences in treatment response to sertraline versus imipramine in chronic depression.

OBJECTIVE: The authors examined gender differences in treatment response to sertraline, a selective serotonin reuptake inhibitor (SSRI), and to imipramine, a tricyclic antidepressant, in chronic depression. METHOD: A total of 235 male and 400 female outpatients with DSM-III-R chronic major depression or double depression (i.e., major depression superimposed on dysthymia) were randomly assigned to 12 weeks of double-blind treatment with sertraline or with imipramine after placebo washout. RESULTS: Women were significantly more likely to show a favorable response to sertraline than to imipramine, and men were significantly more likely to show a favorable response to imipramine than to sertraline. Gender and type of medication were also significantly related to dropout rates; women who were taking imipramine and men who were taking sertraline were more likely to withdraw from the study. Gender differences in time to response were seen with imipramine, with women responding significantly more slowly than men. Comparison of treatment response rates by menopausal status showed that premenopausal women responded significantly better to sertraline than to imipramine and that postmenopausal women had similar rates of response to the two medications. CONCLUSIONS: Men and women with chronic depression show differential responsivity to and tolerability of SSRIs and tricyclic antidepressants. The differing response rates between the drug classes in women was observed primarily in premenopausal women. Thus, female sex hormones may enhance response to SSRIs or inhibit response to tricyclics. Both gender and menopausal status should be considered when choosing an appropriate antidepressant for a depressed patient.

Gender differences in chronic major and double depression.

BACKGROUND: While the sex difference in prevalence rates of unipolar depression is well established, few studies have examined gender differences in clinical features of depression. Even less is known about gender differences in chronic forms of depression. METHODS: 235 male and 400 female outpatients with DSM-III-R chronic major depression or double depression (i.e., major depression superimposed on dysthymia) were administered an extensive battery of clinician-rated and self-report measures. RESULTS: Women were less likely to be married and had a younger age at onset and greater family history of affective disorder compared to men. Symptom profile was similar in men and women, with the exception of more sleep changes, psychomotor retardation and anxiety/somatization in women. Women reported greater severity of illness and were more likely to have received previous treatment for depression with medications and/or psychotherapy. Greater functional impairment was noted by women in the area of marital adjustment, while men showed more work impairment. LIMITATIONS: Since our population consisted of patients enrolling in a clinical trial, study exclusion criteria may have affected gender-related differences found. CONCLUSIONS: Chronicity of depression appears to affect women more seriously than men, as manifested by an earlier age of onset, greater family history of affective disorders, greater symptom reporting, poorer social adjustment and poorer quality of life. These findings represent the largest study to date of gender differences in a population with chronic depressive conditions.

Lost human capital from early-onset chronic depression.

OBJECTIVE: Chronic depression starts at an early age for many individuals and could affect their accumulation of "human capital" (i.e., education, higher amounts of which can broaden occupational choice and increase earnings potential). The authors examined the impact, by gender, of early- (before age 22) versus late-onset major depressive disorder on educational attainment. They also determined whether the efficacy and sustainability of antidepressant treatments and psychosocial outcomes vary by age at onset and quantified the impact of early- versus late-onset, as well as never-occurring, major depressive disorder on expected lifetime earnings. METHOD: The authors used logistic and multivariate regression methods to analyze data from a three-phase, multicenter, double-blind, randomized trial that compared sertraline and imipramine treatment of 531 patients with chronic depression aged 30 years and older. These data were integrated with U.S. Census Bureau data on 1995 earnings by age, educational attainment, and gender. RESULTS: Early-onset major depressive disorder adversely affected the educational attainment of women but not of men. No significant difference in treatment responsiveness by age at onset was observed after 12 weeks of acute treatment or, for subjects rated as having responded, after 76 weeks of maintenance treatment. A randomly selected 21-year-old woman with early-onset major depressive disorder in 1995 could expect future annual earnings that were 12%-18% lower than those of a randomly selected 21-year-old woman whose onset of major depressive disorder occurred after age 21 or not at all. CONCLUSIONS: Early-onset major depressive disorder causes substantial human capital loss, particularly for women. Detection and effective treatment of early-onset major depressive disorder may have substantial economic benefits.

Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: A 6-month randomized controlled trial.

CONTEXT: Generalized anxiety disorder (GAD) is a chronic disorder that is associated with debilitating psychic and somatic symptoms. Venlafaxine extended-release (XR) capsules have been shown to be effective in short-term treatment of patients with GAD without major depressive disorder (MDD), but long-term data are needed to establish whether this agent confers persistent benefits. OBJECTIVE: To compare the 6-month efficacy and safety of a flexible dosage of venlafaxine XR in outpatients with GAD without associated MDD. DESIGN: Six-month, randomized, double-blind, placebo-controlled, parallel-group trial conducted May 1996 to October 1997. SETTING: Fourteen outpatient clinics and private psychiatric practices in the United States. PARTICIPANTS: A total of 251 outpatients aged 18 years or older who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for GAD, had sufficient symptoms to require treatment, and did not have coexisting MDD. INTERVENTIONS: Participants were randomly assigned to receive either placebo (n=127) or venlafaxine XR (75, 150, or 225 mg/d, as required to control symptoms; n=124) for 28 weeks. MAIN OUTCOME MEASURES: Changes from baseline in the Hamilton Rating Scale for Anxiety (HAM-A) total score, the HAM-A psychic anxiety factor score, and the Clinical Global Impressions (CGI) scale Severity of Illness and Global Improvement scores, compared by intervention group. RESULTS: During weeks 6 through 28, response rates in the venlafaxine XR group were 69% or higher compared with rates of 42% to 46% in the placebo group (P<.001). By an evaluable-patient analysis, venlafaxine XR compared with placebo significantly improved anxiety scores from week 1 or 2 through week 28 on all primary efficacy measures, including the HAM-A total (P<.001), the HAM-A psychic anxiety factor (P<.001), and the CGI scale scores (P<.001). Adjusted mean changes from baseline to week 28 using last-observation-carried-forward methods were for HAM-A, venlafaxine XR -13.4, placebo -8.7 (P<.001); for HAM-A psychic anxiety score, venlafaxine XR -7.4, placebo -4.2 (P<.001); and for CGI-Improvement, venlafaxine XR 2.2, placebo 3.0 (P<.001). The most common treatment-emergent adverse event was nausea, followed by somnolence and dry mouth. CONCLUSIONS: This study is the first placebo-controlled demonstration of the long-term efficacy of any drug class in treating outpatients with DSM-IV-diagnosed GAD. Venlafaxine XR is an effective, rapidly acting, safe, once-daily agent for both the short- and long-term treatment of anxiety and may provide an important alternative to currently available anxiolytics. JAMA. 2000.

Mirtazapine substitution in SSRI-induced sexual dysfunction.

BACKGROUND: Sexual side effects are a common and bothersome reaction to selective serotonin reuptake inhibitors (SSRIs), frequently leading to cessation of treatment. Mirtazapine, an alpha2-adrenoceptor and serotonin-2/3 receptor antagonist, appears to cause few sexual problems. METHOD: Nineteen patients (12 women and 7 men), with SSRI-induced sexual dysfunction who were in remission from major depressive disorder (total Hamilton Rating Scale for Depression [HAM-D] score < or = 10), were switched to open-label mirtazapine for up to 6 weeks. Mirtazapine was titrated from 7.5 mg to 45 mg daily, as tolerated. Sexual functioning was measured weekly with the Arizona Sexual Experiences Scale (ASEX), and depression was measured weekly with the HAM-D. RESULTS: Eleven patients (58%) had a return of normal sexual functioning (mean +/- SD ASEX score = 12+/-3), and another 2 (11%) reported significant improvement in sexual functioning (mean ASEX score reduced from 24+/-1 to 20+/-0). All nineteen patients maintained their antidepressant response (HAM-D score after 6 weeks of mirtazapine = 6+/-3). The most commonly reported side effects (using moderate/severe rating on a symptom checklist) were initial sedation (N = 3), irritability (N = 6), and muscle soreness and stiffness (N = 3). Weight gain of 10 to 20 lb (4.5-9 kg) was seen in 3 patients (2 women and 1 man). CONCLUSION: Mirtazapine is an effective antidepressant for many patients experiencing SSRI-induced sexual dysfunction.

A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression.

BACKGROUND: Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain. METHODS: We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone (maximal dose, 600 mg per day), the cognitive behavioral-analysis system of psychotherapy (16 to 20 sessions), or both. At base line, all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression (indicating clinically significant depression). Remission was defined as a score of 8 or less at weeks 10 and 12. For patients who did not have remission, a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less. Raters were unaware of the patients' treatment assignments. RESULTS: Of the 681 patients, 662 attended at least one treatment session and were included in the analysis of response. The overall rate of response (both remission and satisfactory response) was 48 percent in both the nefazodone group and in the psychotherapy group, as compared with 73 percent in the combined-treatment group. (P<0.001 for both comparisons). Among the 519 subjects who completed the study, the rates of response were 55 percent in the nefazodone group and 52 percent in the psychotherapy group, as compared with 85 percent in the combined-treatment group (P<0.001 for both comparisons). The rates of withdrawal were similar in the three groups. Adverse events in the nefazodone group were consistent with the known side effects of the drug (e.g., headache, somnolence, dry mouth, nausea, and dizziness). CONCLUSIONS: Although about half of patients with chronic forms of major depression have a response to short-term treatment with either nefazodone or a cognitive behavioral-analysis system of psychotherapy, the combination of the two is significantly more efficacious than either treatment alone.

The Arizona Sexual Experience Scale (ASEX): reliability and validity.

Although sexual dysfunction is common in psychiatric patients, quantification of sexual dysfunction is limited by the paucity of validated, user-friendly scales. In order to address this problem, the authors have developed the Arizona Sexual Experiences Scale (ASEX), a five-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Possible total scores range from 5 to 30, with the higher scores indicating more sexual dysfunction. This study assesses the internal consistency, test-retest reliability, and convergent and discriminant validity of the ASEX.

Serum lithium levels and the outcome of maintenance therapy of bipolar disorder.

A literature review was conducted to locate studies that compared different serum lithium levels in the long-term treatment of patients with bipolar disorder and articles about factors that may affect serum lithium levels. Patients with bipolar disorder on long-term treatment with lithium are typically maintained at serum lithium concentrations between 0.6 and 1.0 mEq/L. Although there are individual exceptions, serum lithium levels below 0.6 mEq/L have been shown in controlled clinical trials to be less effective in preventing relapses than levels within this range, whereas levels much above 1.2 mEq/L can lead to toxicity. Differences in efficacy between levels within the accepted range have not been established. However, higher levels are associated with greater side effects, which can lead to poor compliance. Interindividual variation in pharmacokinetics and pharmacodynamics, as well as such external factors as diet and concomitant medications, can affect serum lithium levels.

Pharmacologic treatment of depression during pregnancy.

CONTEXT: Despite the frequency of depression in women of childbearing age, information to guide patients and physicians through a consideration of treatment during pregnancy is limited. OBJECTIVE: To identify risk factors associated with treatment of major depression during pregnancy to help physicians develop treatment plans that optimize clinical care. DATA SOURCES: Reports of prospective controlled trials in English were identified from MEDLINE and Health STAR using the search terms antidepressant during pregnancy and depression during pregnancy, by manually searching bibliographies of review articles, and through discussions with investigators for 1989-1999. STUDY SELECTION: We selected studies in which maternal and infant health outcomes associated with antidepressant exposure were compared with those of non-teratogen-exposed controls. Four studies published since 1993 were identified and included in the analysis. DATA EXTRACTION: We abstracted information about identification of subjects, comparison groups, pregnancy, and birth outcomes. We organized the data along 5 domains of reproductive toxicity: intrauterine fetal death, morphologic teratogenicity, growth impairment, behavioral teratogenicity, and neonatal toxicity. DATA SYNTHESIS: Data were available for tricyclic antidepressants (collectively), fluoxetine, and newer selective serotonin reuptake inhibitors (collectively). Exposure to these agents did not increase risk for intrauterine death or major birth defects. Decreased birth weights of infants exposed to fluoxetine in the third trimester were identified in 1 study. The development of children whose mothers took tricyclics or fluoxetine during gestation did not differ from that of controls. Direct drug effects and withdrawal syndromes occurred in some neonates whose mothers were treated with antidepressants near term. CONCLUSIONS: Although few in number, new information from prospective studies provides a welcome change from decision making based on nonprospective data. Monitoring and interventions for patients with identified risks (eg, poor weight gain) are recommended.

Tryptophan depletion and depressive vulnerability.

BACKGROUND: Rapid and transient depletion of tryptophan (TRP) causes a brief depressive relapse in most patients successfully treated with and taking selective serotonin reuptake inhibitors, but little change in drug-free, symptomatic depressed patients. This study investigates the effects of TRP depletion in drug-free subjects in clinical remission from a prior major depressive episode (MDE). METHODS: Twelve subjects with a prior MDE, currently in clinical remission and drug-free for at least 3 months (patients), and 12 healthy subjects without personal or family history of Axis I disorder (controls), received TRP depletion. The study was conducted in a double-blind, controlled [full (102-g) and quarter-strength (25 g) 15-amino acid drinks], crossover fashion. Behavioral ratings and plasma TRP levels were obtained prior to, during, and after testing. RESULTS: All subjects experienced significant depletion of plasma TRP on both test-drinks, showing a significant dose-response relation. Healthy control subjects had minimal mood changes, but patients had a depressive response of greater magnitude. CONCLUSIONS: In the context of prior TRP depletion studies with antidepressant-treated, and drug-free symptomatic depressed patients, these results suggest that depression may be caused not by an abnormality of 5-HT function, but by dysfunction of other systems or brain regions modulated by 5-HT.

Sexual dysfunction secondary to depressive disorders.

Human sexuality has received less systematic study and is less well understood than other aspects of mental and physical health. Although depression itself, apart from medication, is generally believed to be associated with sexual dysfunction, the few existing studies report wide discrepancies with regard to frequency, gender, and quality of sexual dysfunction. Loss of libido is frequently and consistently associated with major depression. Moreover, sexual dysfunction secondary to depression or other factors is often mistaken for that caused by antidepressant medication. Although antidepressants have long been associated with sexual dysfunction, the precise nature and magnitude of sexual side effects have not been fully appreciated. This article will review the literature on sexual dysfunction associated with unmedicated depression and offer a guide for the clinician evaluating and treating depressed patients with sexual problems.