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

Formulary restriction of selective serotonin reuptake inhibitors for depression: potential pitfalls.

The American healthcare market is currently estimated at more than 900 billion US dollars with double digit rising costs per year. Psychotropic agent costs have more than kept pace with market increases. Medication acquisition costs are an obvious focus for limiting costs in various care systems. Restrictive formularies are a common method of attempting to limit costs. To support our opinion that a single agent is ill advised, we explored the available evidence on the intended and unintended consequences of having a single or exclusive selective serotonin reuptake inhibitor (SSRI) on a formulary. Central to this position is an assumption of the interchangeability of SSRIs; we examined the evidence for and against this through a model to determine the probability of interchangeability. We conclude that the practice of having a single SSRI on the formulary for a healthcare plan seems ill founded. Patients who switch antidepressants remain in treatment 50% longer and cost approximately 50% more to treat in a more costly treatment setting. Giving the primary care physician several antidepressant choices can provide more options to continue treatment of his or her patient in the less expensive primary care setting. In terms of cost containment, formulary restrictions are far more likely to have the opposite effect.

Efficacy of sildenafil citrate for the treatment of erectile dysfunction in men taking serotonin reuptake inhibitors.

OBJECTIVE: This study was an evaluation of whether sildenafil citrate is effective for the treatment of erectile dysfunction in men taking concomitant serotonin-reuptake-inhibiting antidepressants. METHOD: A retrospective subanalysis of combined data from 10 phase II/III double-blind, placebo-controlled, fixed- and flexible-dose trials (12-26 weeks) identified a group of men with erectile dysfunction receiving 5 to 200 mg/day of sildenafil (N=65) or placebo (N=33) and concomitant serotonin-reuptake-inhibiting antidepressants. Efficacy was measured by responses to questions from the International Index of Erectile Function on ability to achieve erection, ability to maintain erection, ejaculation frequency, orgasm frequency, and sexual desire. RESULTS: Patients with erectile dysfunction receiving sildenafil and concomitant serotonergic antidepressants had significantly greater improvements in ability to achieve and maintain an erection, frequency of ejaculation, and orgasm frequency than did patients receiving placebo, without increased sexual desire. CONCLUSIONS: Sildenafil significantly improved erectile dysfunction in patients taking concomitant serotonergic antidepressants.

Managing treatment-emergent sexual dysfunction associated with serotonergic antidepressants: before and after sildenafil.

Sexual dysfunction is a common and troublesome side effect associated with selective serotonin reuptake inhibitors and other antidepressants that reportedly occurs in 40%-70% of patients prescribed selective serotonin reuptake inhibitors. Management of this iatrogenic condition has relied on "clinical wisdom" derived over decades primarily from open-label, non-placebo-controlled, selected case and literature review studies. Management approaches fall into four broad categories: 1) antidote, 2) avoidance, 3) augmentation/switching, and 4) adaptation. Until the development of sildenafil (Viagra), none of the existing managements demonstrated clear efficacy in systematic, double-blind, placebo-controlled trials. Renewed interest in treatment-associated sexual dysfunction emerged because of advances in our knowledge of the biological mechanisms of sexual functioning, awareness that sexual dysfunction compromises patient adherence to treatment, and an improved focus on improving disease management outcomes of depression. Recent placebo-controlled studies provide evidence for questioning the effectiveness of earlier approaches to the management of sexual dysfunction side effects, and suggest improved treatment options with sildenafil. Effective management of treatment-emergent sexual dysfunction is a medical necessity in order to prevent relapse and recurrence of serious disorders such as major depression, which are highly treatment responsive but frequently compromised by medication noncompliance due to side effects such as sexual dysfunction.

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.

Theoretical and methodological issues in psychiatric comorbidity.

The occurrence of multiple diagnoses in one patient is a phenomenon of major clinical and theoretical importance. This paper reviews the various factors involved in real and artifactual comorbidity. Important causes of spurious comorbidity are discussed, including invalidity of the individual diagnoses, use of inappropriate diagnostic paradigms, descriptive overlap of diagnostic criteria, ascertainment bias, and diagnostic bias. To illustrate some of the concepts discussed, two examples are presented: the comorbidity of schizophrenia and substance use disorders, and the comorbidity of posttraumatic stress disorder and major depression. The study of comorbidity can advance psychiatry by helping us to clarify our thinking about categories of illness and the boundaries between them, as well as the relationships among these categories.

Identifying personality disorders: towards the development of a clinical screening instrument.

The study objective was to identify a set of personality disorder (PD) criteria from the DSM PD diagnostic sets that can be used to detect subjects with an increased likelihood of having a PD diagnosis. In a series of outpatients evaluated systematically in two waves for every criteria item for 12 DSM-III-R PDs, stepwise logistic regression identified 45 criteria as discriminative for their specific PDs, which are selected for further analysis to assess their ability to discriminate for any PD. Receiver operating characteristic (ROC) analysis is used to evaluate their discriminative power in an independent conjoined sample (N = 1,342) from six centers that assessed every PD criteria item by structured instrument (Structured Clinical Interview for DSM-III-R PDs [SCID-II, Personality Disorder Examination [PDE], and Structured Interview for DSM-III-R PDs [SIDP-R]). The cutoff that maximizes information gain is used to determine the diagnostic threshold (DT). Initially, 15 of 45 criteria are identified. At the 0.43 PD prevalence, a DT of 2 or more of the 15 PD criteria across samples is optimal. The maximum information gain (MIG) is .42 bits, and the AUR is 0.94+/-.007. Other performance indices at this cutoff are .90 sensitivity, .84 specificity, .81 positive predictive power (PPP), .91 negative predictive power (NPP), and .86 hit rate (HR). Taken collectively, the 15 PD criteria selected by the data reduction techniques suggest a narrowed set to be assessed in screening for the presence or absence of any PD with comparable or better psychometric properties than other tests routinely used for diagnosing medical and psychiatric disorders. If specific PD categorization is needed, a second-step comprehensive assessment should follow.

Modeling the pharmacoeconomic cost of three selective serotonin reuptake inhibitors.

The authors present a method for modeling cost data on three selective serotonin reuptake inhibitors (SSRIs)-fluoxetine, paroxetine, and sertraline-from a large clinical outcomes study in a university-affiliated mental health center. Using data from 2,779 patients, average drug cost per day was calculated based on the percentage of patients on each daily dose of each medication. Given no overall significant difference between the SSRIs in effectiveness, the actual average cost per day determined by dose distribution was $1.79 for fluoxetine, $1.41 for paroxetine, and $1.21 for sertraline (using halved 100 mg tablets). The results suggest that cost can serve as one measure to help guide choice of medications.

Antidepressant medication change in a clinical treatment setting: a comparison of the effectiveness of selective serotonin reuptake inhibitors.

BACKGROUND: This investigation focuses on the 3 most frequently used selective serotonin reuptake inhibitors (SSRIs) (paroxetine, fluoxetine, sertraline) and examines the rate of medication switches as a measure of effectiveness. We answer 2 questions: (1) What is the likelihood that a patient starting treatment with an SSRI will complete treatment with the same agent? and (2) Depending on the initial SSRI agent used, do patients switch at different frequencies? METHOD: A retrospective chart review was performed on 2779 patients treated in a university outpatient clinic from March 1995 to January 1997. Of these, 263 patients given antidepressants were randomly selected: 214 were prescribed SSRIs; 24, novel antidepressants; and 25, tricyclic antidepressants. RESULTS: There was no significant difference in rate of switching between the different classes of antidepressant (p = .1) nor between drugs within the SSRI class (p = .513). When medication change was the independent factor, significant differences between the groups were total time in treatment and number of visits (p < .001 and p = .011, respectively). Age, education, and Clinical Global Impressions-Severity of Illness scale scores (admission, discharge, and change) were not significantly different between the groups. CONCLUSION: Approximately 25% of patients started with an SSRI will switch to another antidepressant in the course of their treatment. The SSRIs appear to be equivalent in effectiveness. They are not interchangeable, because patients who discontinue one SSRI for lack of tolerability or response can generally be treated effectively with another.

Sildenafil for women patients with antidepressant-induced sexual dysfunction.

In an open study, sildenafil (Viagra) was prescribed for nine women outpatients who reported sexual dysfunction induced by antidepressant medication, primarily selective serotonin reuptake inhibitors. A 50 mg dose of sildenafil was prescribed, and patients were instructed to take it approximately one hour before sexual activity. They were told to increase the dose to 100 mg on the next occasion if they experienced a partial response or a lack of response to sildenafil. The nine patients, all of whom had experienced either anorgasmia or delayed orgasm with or without associated disturbances, reported significant reversal of sexual dysfunction, usually with the first dose of 50 mg of sildenafil.

Sildenafil for iatrogenic serotonergic antidepressant medication-induced sexual dysfunction in 4 patients.

OBJECTIVE: To evaluate the effect of sildenafil on iatrogenic serotonergic antidepressant-induced sexual dysfunction. METHOD: Four outpatients (2 men, 2 women) who developed sexual dysfunction (erectile impotence, anorgasmia) during treatment with a serotonin reuptake inhibitor antidepressant for psychiatric disorder were selected. Each subject was initially prescribed sildenafil 50 mg to be taken approximately 1 hour before sexual activity. The dose was increased to 100 mg for a partial or failed response. RESULTS: Four cases are detailed in case report fashion. All 4 had rapid reversal of their sexual dysfunction, usually with the first dose. Reversal equates to 1 successful use of sildenafil in each of 2 patients and 3 uses in 2 patients. CONCLUSION: Sildenafil may be an effective treatment for serotonergic antidepressant-induced sexual dysfunction and deserves further evaluation in randomized placebo-controlled studies.

A mathematical typology analysis of DSM-III-R personality disorder classification: grade of membership technique.

This study employed grade of membership (GoM) analysis in a clinical setting to determine if the DSM-III-R personality disorder (PD) diagnostic criteria cluster into recognizable disorders resembling the official axis II nosology. The GoM model, based on fuzzy-set theoretic concepts, explicitly examines medical diagnostic systems by quantitatively identifying and characterizing subpatterns of illness within a broad class. A semistructured assessment of 110 outpatients was performed for 12 PDs and their 112 diagnostic criteria. GoM analysis was performed using internal variables of the 112 PD criteria rated as present or absent. Demographic variables, axis I and II diagnosis (structured clinical Interview for DSM [SCID]), and treatment response (Global Adjustment Scale [GAS]) information were used as external validators. Four pure types (PT) provided the most satisfactory solution to the data. PT-I is characterized by marked maladaptive personality pathology, which is manipulative, egocentric, impulsive, and alloplastic. PT-II consists primarily of exaggerated socially anxious and detached traits. PT-III is sociably dependent and autoplastic. PT-IV is essentially asymptomatic. GoM provides a more parsimonious handling of the PD criteria than provided by classifying according to DSM categories. The analysis fails to confirm the natural occurrence of any single specific axis II PD or cluster.

Consideration of the relevance of ethological animal models for human repetitive behavioral spectrum disorders.

Treatment successes of various stereotyped behaviors in animals and humans has renewed interest in ethologic animal models for the study of psychiatric disorders. This report presents another such behavior occurring in horses to weaving. This anomalous, repetitive, and purposeless behavior draws analogies to human compulsive spectrum behaviors. A "weaver" provided an opportunity to evaluate serotonin, dopamine, and opioid neurotransmitter system contributions by probing each with a selective agent in A-B-A-C-A-D design. The horse was treated in sequential 1-month periods separated by 1-month washouts with a serotonin transport inhibitor (SRI), opiate antagonist (OA), and neuroleptic (DA). Videotape was taken weekly and analyzed by two blind raters. Frequency of head swings, latency to onset, and severity were recorded. The SRI showed > 95% symptom reduction, the DA 40%, and OA 30%. The findings suggest that neurochemical explanations of disturbance based on single drug vs. placebo trials may be oversimplified. Multiple-system probes are needed to dissect complex interactive biological systems. Animal model research can have an important role in such investigations.

An empirical method to refine personality disorder classification using stepwise logistic regression modeling to develop diagnostic criteria and thresholds.

This study of DSM-III-R personality disorder (PD) classification provides an empirical approach to determine (1) the discriminative power of each criterion and (2) the optimal number of criteria needed to diagnose the presence of each PD. A semistructured assessment of 110 outpatients was performed for the 11 PDs and their 104 diagnostic criteria. Sensitivity, specificity, and predictive powers were calculated for each criterion item. Logistic regression was performed to determine (1) univariate weightings of the individual criteria as applied to a given diagnosis, and (2) multivariate measures of the criteria that significantly improved the chi-square value in a stepwise fashion. The significant items were then equally weighted to calculate the optimal number needed to diagnose category membership. Of 104 PD criteria, 41 discriminated at a significance level of .05 or less, and each PD could be optimally diagnosed with fewer criteria than currently required. We can empirically reduce the number of criteria combinations comprising individual categories, decrease heterogeneity, and narrow diagnostic boundaries. This increases the likelihood of identifying etiological factors, predictors of clinical course, specific treatments, familial aggregation, and neurobiological correlates for the PD taxa.

A systematic assessment of the comorbidity of DSM-III-R personality disorders in alcoholic outpatients.

To our knowledge, this is the first study to examine the systematic comorbidity of DSM-III-R personality disorders (PDs) in a sample of alcoholic outpatients. The extent and direction of overlap can provide a measure of heterogeneity and descriptive validity. Fifty sober alcoholic outpatients enrolled in a treatment program were assessed by Structured Clinical Interview for DSM-III (SCID) instruments for the presence of axis I and axis II disorders; 80% had either a coexistent axis I or II disorder, with 66% having an axis I disorder, 64% an axis II disorder, and 50% both axis I and II disorders. There were 84 PD diagnoses among the 32 PD patients (2.6/patient), with multiple diagnoses in 20 (62%). The most prevalent PD diagnoses were paranoid (44%), antisocial (20%), avoidant (20%), passive-aggressive (18%), and borderline (16%). Overlap was extensive and not confined to any one of the three designated axis II clusters. Poorer outcome was associated with the presence of PD. Personality variables may offer a means of further characterizing the heterogeneity observed in axis I disorders. Further refinement of the current system of PD classification and investigation into alternate models is needed.

The comorbidity of borderline personality disorder and other DSM-III-R axis II personality disorders.

OBJECTIVE: This study examines the comorbidity of DSM-III-R borderline personality disorder and the other axis II personality disorders. The extent and direction of overlap provides a measure of the clarity of its diagnostic boundaries and descriptive validity. METHOD: In 110 outpatients without concurrent major axis I conditions, axis II diagnoses were assessed in semistructured format and all DSM-III-R personality disorder criteria were rated. Multiple diagnoses were recorded. RESULTS: Twenty-two patients (20%) met criteria for borderline personality disorder; 18 (82%) had at least one additional personality disorder diagnosis. Using measures of frequencies and intercorrelation coefficients, the authors found that overlap was extensive and not confined to any one of the three designated axis II clusters. Factor analysis revealed 1) a group containing borderline personality disorder with paranoid, histrionic, narcissistic, antisocial, and passive-aggressive personality disorders and 2) another grouping of schizoid, schizotypal, avoidant, obsessive-compulsive, and self-defeating personality disorders. CONCLUSIONS: Borderline personality disorder appears to constitute a broad, heterogeneous category with unclear boundaries that embraces a general personality disorder concept. Both further refinement of the borderline personality disorder construct and investigation into alternative models to the DSM-III-R axis II classification system are suggested.

An overview of somatic treatment of psychosis during pregnancy and postpartum.

Treatment and management of the psychotic pregnant patient is insufficiently covered by most standard texts and the current literature. To date, there are no controlled studies on the efficacy of different therapeutic modalities during pregnancy. Medications that have proved effective in the treatment of the various psychoses are not without added risk for the pregnant patient. However, there is no effective medical treatment without attendant risk. Although the psychotic pregnant patient presents a therapeutic dilemma, these patients can be effectively treated by a program that allows for flexibility and innovation within the framework of sound conservative medical practice. Professional territorial difficulties can be avoided by a unified effort.

Abuse of the child and anxiety in the adult.

We report on the early development and family background of 20 patients admitted to an anxiety disorders clinic serving a disadvantaged population. Sixteen of these 20 patients had been abused or neglected. Nineteen had a diagnosis of at least one personality disorder. We discuss the relationship between the patients' backgrounds and their current disorders. It is our thesis that the traumatic background of our patients is the major factor that allows anxiety to be passed across the generations.