Polypharmacy in Maintenance of Bipolar Disorder.

OBJECTIVES: To track the outcomes of bipolar patients who had remitted from an acute manic episode on single- and multiple-drug regimens including lithium (LI), valproate (VPA), and carbamazepine (CBZ), in order to compare relapse rates on 1, 2, or 3 medications. METHODS: Following treatment of an acute manic episode and a 1-month period of no signs of mood episodes, patients were evaluated at 1- to 2-month intervals as to the kind of regimen required to maintain their stability while continuing on this regimen for 2 years. Medication regimens included 1, 2, or 3 of the following drugs: LI, VPA, and/or CBZ. The 3 medication groups were followed from entry into the study through 3 possible end points based on the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition checklist: "NO-Relapse," "Relapse," or "Dropped out." RESULTS: Of the 1312 patients included in the study and followed up for 2 years, 281 patients (21.4%) were maintained on a single drug (LI, VPA, or CBZ), 852 (65%) on 2 drugs, and 179 (13.6%) on 3 or more drugs. A smaller percentage of patients on 1 medication had NO-Relapse for 2 years (22.8%), compared with patients on 2 medications (43.9%) and patients on 3 or more medications (41.9%): χ2 = 40.3, P < 0.001. CONCLUSIONS: This study showed that overall, of the bipolar patients who were asymptomatic at 1 month, a smaller percentage of patients on 1 medication continued to be stable for 2 years, compared with patients on 2 medications and patients on 3 or more medications.

Prophylactic efficacy of lithium, valproic acid, and carbamazepine in the maintenance phase of bipolar disorder: a naturalistic study.

Mood stabilizers are used clinically for the management of bipolar disorder. Prophylactic therapy with mood stabilizers is the primary treatment for preventing depressive and manic relapses in bipolar patients once they are stabilized. In this study, we examined the relative efficacy of the three most commonly used mood-stabilizing agents: lithium (Li), valproic acid (VPA), and carbamazepine (CBZ), in preventing relapse episodes. A total of 225 patients with bipolar disorder were included in the present analysis. Patients taking Li, VPA, or CBZ were followed up for up to 124 months, until suffering a manic, mixed, or depressive episode (relapse), or until the end of the study/study termination (no relapse), whichever came first. The median unadjusted survival time was 36 months for patients taking VPA, 42 months for patients taking CBZ, and 81 months for patients taking Li. These results indicate that patients stayed longer on Li, suggesting that it might have been better tolerated than either CBZ or VPA. χ-Analysis showed that patients taking Li were significantly less likely to experience relapse during the observational period than patients taking either VPA or CBZ (P<0.05). A Cox regression model showed that the hazard of experiencing relapse was significantly predicted by the total number of depressive (P=0.007) and manic symptoms (P=0.02) assessed before the observation period. In addition, after controlling for symptom covariates, the hazard of experiencing relapse was 1.66 times (95% confidence interval 1.03-2.67) or 66% higher for patients taking VPA compared with patients taking Li (P=0.037). Although the hazard of experiencing relapse was higher for patients taking CBZ compared with those taking Li, the risk was not elevated by a significant amount. Notwithstanding the limitations of the naturalistic design of this study, the differences in relapse prevention and survival time observed in these medications show Li fairing relatively better in prophylactic therapy.

Maintenance treatment for obsessive-compulsive disorder: findings from a naturalistic setting.

BACKGROUND: Although the utility of medication in the acute treatment of adult obsessive-compulsive disorder (OCD) is well-established, the role of maintenance therapy is not as well-studied. This study examines the efficacy of long-term treatment for, and predictors of, stability in medicated patients with adult OCD. METHODS: Using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), we retrospectively evaluated 84 OCD patients who responded to a 10- to 12-week, open-label, acute treatment in a naturalistic clinic setting. Patients were followed based on their medication response for 1 to 92 months (mean 34.3), or until they terminated therapy. We evaluated Y-BOCS scores every 6 months or sooner, if clinically indicated. RESULTS: Of the 84 patients, 39 (46.4%) responded, having relapsed within a 5-year period. Predictors of longer duration of stability were adjunctive cognitive-behavioral therapy (CBT), lack of comorbid disorders, lower Y-BOCS score after treatment, and larger decrease in Y-BOCS score during treatment phase. CONCLUSIONS: Our results show the importance of maintenance treatment of OCD, noting the benefits of long-term response to adjunctive CBT and of achieving maximal acute response. It is becoming crucial to develop larger maintenance studies with more uniform design to better assess the natural course of treated OCD and improve treatment strategies.

Prophylactic efficacy of fluoxetine, escitalopram, sertraline, paroxetine, and concomitant psychotherapy in major depressive disorder: outcome after long-term follow-up.

The acute efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder (MDD) is well established; however their role in longer-term prevention of recurrence remains unconfirmed. This study aims at examining: the prophylactic efficacy of four commonly used SSRIs in MDD in a naturalistic setting with long-term follow-up, the effect of concomitant cognitive behavioral therapy (CBT), and the predictors of outcome. In a prospective cohort study, 387 patients who either remitted or responded following treatment with four different SSRIs-fluoxetine, escitalopram, sertraline and paroxetine-were followed up over several years. During an average follow-up period of 34.5 months, 76.5% of patients experienced MDD recurrence. Escitalopram and fluoxetine showed a numerically higher prophylactic efficacy than paroxetine and sertraline but the difference was statistically insignificant. The prophylactic efficacy for SSRI-only treatment was limited, with a recurrence rate of 82.0%, compared to 59.0% of patient recurrence rate in concomitant Cognitive Behavioral Therapy (CBT). The relatively small size of the CBT group and the lack of randomization may undermine the extrapolation of its findings to clinical practice. Nevertheless, the study preliminary data may help in defining the clinical utility of antidepressants and CBT in the prophylaxis from MDD recurrence.

Patient-reported outcomes before and after treatment of major depressive disorder.

Patient reported outcomes (PROs) of quality of life (QoL), functioning, and depressive symptom severity are important in assessing the burden of illness of major depressive disorder (MDD) and to evaluate the impact of treatment. We sought to provide a detailed analysis of PROs before and after treatment of MDD from the large Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. This analysis examines PROs before and after treatment in the second level of STAR*D. The complete data on QoL, functioning, and depressive symptom severity, were analyzed for each STAR*D level 2 treatment. PROs of QoL, functioning, and depressive symptom severity showed substantial impairments after failing a selective serotonin reuptake inhibitor trial using citalopram (level 1). The seven therapeutic options in level 2 had positive statistically (P values) and clinically (Cohen's standardized differences [Cohen's d]) significant impact on QoL, functioning, depressive symptom severity, and reduction in calculated burden of illness. There were no statistically significant differences between the interventions. However, a substantial proportion of patients still suffered from patient-reported QoL and functioning impairment after treatment, an effect that was more pronounced in nonremitters. PROs are crucial in understanding the impact of MDD and in examining the effects of treatment interventions, both in research and clinical settings.

Los resultados percíbidos por el paciente (PROs) sobre la calídad de vida, el funcionamíento y la gravedad de los síntomas depresivos son importantes para la evaluación de la carga de enfermedad y para medír el impacto del tratamíento del trastorno depresívo mayor (TDM). Se íntenta proporcíonar un análísis detallado de los PROs antes y después del tratamíento del TDM a partír del gran estudio STAR*D (Sequenced Treatment Alternatives to Relíeve Depression). Este análísis examina los PROs antes y después del tratamíento en el segundo nivel del STAR*D. Los datos completes sobre calídad de vída, funcíonamíento y gravedad de los síntomas depresivos se analizaron para cada tratamiento del nivel 2 del STAR*D. Los PROs de calídad de vída, funcionamiento y gravedad de los síntomas depresivos mostraron un deterioro significaiivo después de fallar el ensayo con citalopram, un inhibidor selectivo de la recaptura de serotonina (en el nivel 1). Las siete opciones terapéuticas del nivel 2 tuvíeron un ímpacto estadística (valores de p) y clínicamente (diferencías estandarízadas de Cohen [d de Cohen]) signíficativo en cuanto a calídad de vída, funcionamíento, gravedad de los síntomas depresivos y reducción en el cálculo de la carga de enfermedad. No hubo díferencias estadísticamente sígnificatívas entre las intervencíones. Sin embargo, una proporción sígnificativa de pacíentes mantuvo un deterioro en la calídad de vída y el funcíonamíento después del tratamiento, y el efecto fue más pronunciado en aquellos que no remitíeron. Los PROs son clave para la comprensión del impacto del TDM y para examínar los efectos de las intervenciones terapéuticas tanto en investigación como en clínica.

Les résultats rapportés par les patients ou PRO (Patient Reported Outcomes) de qualité de vie (QdV), de fonctionnement, et de sévérité du symptôme dépressif sont importants dans l'évaluation du fardeau de l'épisode dépressif majeur (EDM) et de l'impact du traitement. Nous avons cherché à analyser de façon détaillée les PRO avant et après le traitement d'un EDM au cours de la deuxième étape de la grande étude STAR*D (Sequenced Treatment Alternatives to Relieve Depression). Les données complètes de QdV, fonctionnement et sévérité du symptôme dépressif sont analysées pour chaque traitement de l'étape 2 de STAR*D. Dans l'étape 1 de l'étude, après l'échec du citalopram, un inhibiteur sélectif de recapture de la sérotonine, les PRO de QdV, de fonctionnement et de sévérite du symptôme dépressif étaient très médiocres. L'impact des sept choix thérapeutiques de l'étape 2 sur la QdV, le fonctionnement, la sévérité du symptôme dépressif et la diminution du fardeau calculé de la maladie, a montré des différences statistiquement (valeurs de p) et cliniquement (différences standardisées de Cohen [d de Cohen]) positives. Il n'y a pas de différences statistiquement significatives entre les traitements. Une proportion importante de patients continue néanmoins à souffrir après le traitement, selon les résultats déclarés par les patients sur la QdV et le fonctionnement, et de façon plus prononcée chez ceux qui ne sont pas en rémission. Les PRO sont essentiels pour comprendre l'impact de l'EDM et pour observer les effets du traitement, à la fois pour la recherche et la pratique clinique.

The discrepancy between patients and informants on clinician-rated measures in major depressive disorder: implications for clinical trials and clinical practice.

Clinician-rated measures are used in clinical trials and measurement-based clinical care settings to assess baseline symptoms and treatment outcomes of major depressive disorder (MDD), with a widely held dictum that they are sufficient in assessing the patient's clinical status. In this study, we examined clinician-rated measures of depressive and global symptom severity, obtained by interviewing patients as well as informants in an attempt to examine the potential difference or similarity between these two sources of information. The sample consisted of 89 treatment seeking, DSM-IV diagnosed MDD outpatients treated between 1995 and 2004. The clinician-rated measures used included the Montgomery Åsberg Depression Rating Scale (MADRS), and the Clinical Global Impression Scale (CGI) for Severity. The scores of the clinician-rated measures collected from patients' interviews were compared with those collected from informants' interviews. Clinician-rated scores, collected by interviewing patients, were significantly higher and indicative of greater symptom severity when compared with those collected by interviewing informants. This was true for both the MADRS before (P<0.0001) and after treatment scores (P<0.0001), as well as the CGI before (P<0.0001) and after treatment scores (P<0.0001). Consistently involving informants and the time/burden it takes for them to participate might not be practical in MDD clinical trials or everyday clinical care. The discrepancies observed between the clinician-rated scores obtained from patients and informants emphasize the importance of incorporating collateral information during the assessment and rating of depressive symptom severity in both clinical trials as well as in clinical practice.

Patient-reported outcomes of quality of life, functioning, and depressive symptom severity in major depressive disorder comorbid with panic disorder before and after SSRI treatment in the star*d trial.

BACKGROUND: Panic disorder (PD) is highly comorbid with major depressive disorder (MDD) with potential impact on patient-reported outcomes of quality of life (QOL), functioning, and depressive symptom severity. METHODS: Using data from the sequenced treatment alternatives to relieve depression (STAR*D) trial, we compared entry and post-SSRI-treatment QOL, functioning, and depressive symptom severity scores in MDD patients with comorbid PD (MDD+PD) to MDD patients without PD (MDDnoPD). We also compared pre- and posttreatment proportions of patients with severe impairments in quality of life and functioning. RESULTS: MDD+PD patients experienced significantly lower QOL and functioning and more severe depressive symptoms than MDDnoPD patients at entry. Following treatment with citalopram, both groups showed significant improvements, however, nearly 30-60% of patients still suffered from severe quality of life and functioning impairments. MDD+PD patients exited with lower QOL and functioning than MDDnoPD patients, a difference that became statistically insignificant after adjusting for baseline measures of depressive symptom severity, functioning, and QOL, comorbid anxiety disorders (PTSD, GAD, social, and specific phobias), age, and college education. CONCLUSIONS: Functional outcomes using QOL and functioning measures should be utilized in treating and researching MDD so that shortfalls in traditional treatment can be identified and additional interventions can be designed to address severe baseline QOL and functioning deficits in MDD comorbid with PD.

Scopolamine as an antidepressant: a systematic review.

OBJECTIVES: The cholinergic-adrenergic hypothesis of mania and depression states that depression is characterized by an increase in central cholinergic activity relative to noradrenergic tone. Scopolamine is a centrally acting competitive inhibitor of the muscarinic cholinergic receptor site. This review seeks to find all available data investigating scopolamine as an antidepressant. METHODS: A systematic review of all the published and unpublished or ongoing literature was conducted via Ovid MEDLINE. Keywords used for the search were "scopolamine hydrobromide" in association with one of the following: "depression," "antidepressive agents," "depressive disorder," "depression, chemical," and "affect." PubMed was also searched using "scopolamine" (all fields) and "antidepressant" (all fields) or "depression" (all fields). RESULTS: A small study with elderly patients failed to show a statistically significant improvement in depression when measured at 120 minutes after infusion. A second small, well-controlled study using intramuscular scopolamine showed a small but statistically significant improvement in depression on the morning after the second dose was received. Two double-blind randomized placebo-controlled crossover trials with intravenous scopolamine 4.0 µg/kg infusions showed a significant improvement in depressive symptoms seen as soon as 3 days after the first treatment. Further data analyses showed a greater antidepressant effect in women, significant improvements in bipolar depression, and 85% success rates predicting who will respond to treatment. CONCLUSIONS: Scopolamine is an effective and rapid antidepressant in both unipolar and bipolar depression, working as quickly as 3 days after initial infusion. Independent replication would greatly enhance the literature.

Discontinuation of maintenance selective serotonin reuptake inhibitor monotherapy after 5 years of stable response: a naturalistic study.

OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) are effective treatments of major depressive disorder (MDD), but data to guide the duration of maintenance therapy in community settings are limited. We assessed whether extending maintenance beyond 5 years provided additional benefit and identified other predictors of outcome. METHOD: All patients treated at an urban community outpatient clinic between June 1993 and September 2005 were considered for inclusion in this study. Based upon patient preference and clinician judgment, 60 patients with DSM-IV MDD elected to continue, and 27 patients to discontinue, SSRI treatment after 5 years of clinical stability on maintenance monotherapy in a community clinic. Differences in relapse risk were assessed using the Kaplan-Meier product limit method, and risk factors were evaluated in Cox proportional hazards regression, based on up to 8 years of illness course. RESULTS: Subjects who continued on SSRI treatment experienced a survival probability of maintaining remission during the first year, which was twice that of discontinued subjects (0.79 vs. 0.40), and survival differences persisted for over 30 months. Median survival time until relapse for patients who continued SSRIs was 38 months, exceeding the 10-month survival time of patients who discontinued. After controlling for significant covariates, the hazard ratio for SSRI discontinuation was 4.9. Residual depressive symptoms conferred increased relapse risk, while age, gender, SSRI type and dose, and prior depressive episodes did not predict relapse. CONCLUSION: After 5 years of maintenance monotherapy for MDD, SSRI discontinuation in a community setting is associated with a far poorer illness course than continued maintenance. Discontinuation of long-term maintenance is most likely to be successful in patients with minimal residual symptoms, and discontinued patients should be carefully monitored.

Schizoaffective disorder: diagnostic issues and future recommendations.

OBJECTIVE: Difficulties surrounding the classification of mixed psychotic and affective syndromes continue to plague psychiatric nosology. This paper addresses the controversy regarding the diagnostic validity of schizoaffective disorder (SAD), a diagnosis that is used in both DSM-IV and ICD-10 and one that encroaches on both schizophrenia (SCZ) and bipolar disorder (BD). METHODS: A systematic synthesis of clinical and empirical literature, including evidence from cognitive, neurobiological, genetic, and epidemiological research, was undertaken with the aim of evaluating the utility of the SAD classification. RESULTS: Distinctions between the diagnostic categories of SCZ, SAD and BD are not clearly demarcated by findings from neuropsychological, neuroimaging, molecular neurobiology, or genetic epidemiology studies. On the contrary, convergent evidence purports overlap across current diagnostic boundaries in the heritability and pathophysiology of psychotic and affective disorders. However, there are some disorder-specific findings. CONCLUSIONS: Schizoaffective disorder is a prototypic boundary condition that epitomizes the pitfalls of the current categorical classification system. Future revisions to the DSM should consider the implementation of one of two alternative models to account for individuals presenting with mixed psychotic and affective symptoms. These include the views that (i) SAD is a comorbid set of symptoms that occur as a by-product of two separate disorders (SCZ and BD) or, that (ii) SAD exists as the mid-point on a continuum between SCZ and BD, such that the incorporation of these two disorders onto one dimension may be a suitable alternative. Hence the category SAD should be omitted in future revisions of DSM, allowing the development of meaningful nomenclature that rests upon further rigorous investigation of differences and similarities between disorders.

Teaching psychopharmacology: what works and what doesn't.

How do we best teach clinical psychopharmacology to trainees and clinicians, so they not only increase their knowledge base, but even more importantly also learn to practice the most informed, evidence-based practice possible? This article attempts to answer this elusive question by compiling the individual and combined wisdom of 5 expert psychopharmacology teachers, each of whom draws on years of their own experiences as master educators. The topics covered include teaching clinical psychopharmacological competence in adult psychiatry residency training and in issues specific to both pediatric and geriatric populations, teaching physicians to improve clinical outcomes through continuing medical education, and new developments in adult-centered pedagogy and assessment. Although the focus of this article is on practical pearls found useful in teaching psychiatric residents and practicing physicians, the lessons learned are applicable to other groups of learners such as medical students, other trainees, and nonmedical clinicians. Our goal is to help educators produce competent psychopharmacology clinicians schooled in the latest evidence, capable of keeping up with new knowledge as it becomes available, and practicing both the art and science of expert clinical care.

Three-year medication prophylaxis in panic disorder: to continue or discontinue? A naturalistic study.

OBJECTIVE: Little is known about maintenance treatment for panic disorder. The purpose of this naturalistic study is to compare outcomes of remitted panic disorder patients continued on versus those successfully discontinued from maintenance medication. METHODS: After 3 years of sustained remission with medication in a naturalistic setting, 168 patients were continued on, whereas 37 successfully discontinued from medication. Continued and discontinued groups were followed for an additional 4 to 8 years and compared for differences in treatment outcome using chi(2) and Wilcoxon rank sum tests. Times to relapse were analyzed using the Kaplan-Meier product-limit method, and risk factors for relapse were assessed using Cox proportional hazards regression. RESULTS: The discontinued group was healthier at baseline but had a significantly worse outcome compared with the continued group. Panic-free survival probabilities for the continued group at 1, 2, 3, and 4 years were 0.87, 0.81, 0.71, and 0.64, respectively, and were significantly higher than respective probabilities of 0.53, 0.35, 0.29, and 0.15 for the discontinued group. Median survival time in the continued group was significantly longer, at 5.67 years, than in the discontinued group, at 1.17 years. Cognitive behavioral therapy significantly reduced hazard in the discontinued but not in the continued group. Residual symptoms in either group at time of assignment predicted poorer outcome. CONCLUSION: Our small study suggests that relapse of panic disorder in routine clinical practice occurs even after long-standing remission on maintenance medication, and that relapse risk appears to be markedly higher after medication discontinuation. Discontinuation may be more successful in candidates who received cognitive behavioral therapy and have minimal residual symptoms.