No abstract

Background Although many studies suggest that, on average, depression-specific psychotherapy and antidepressant pharmacotherapy are efficacious, we know relatively little about which patients are more likely to respond to one versus the other. We sought to determine whether measures of spectrum psychopathology are useful in deciding which patients with unipolar depression should receive pharmacotherapy vs. depression-specific psychotherapy. Methods 318 adult outpatients with major depression were randomly assigned to escitalopram pharmacotherapy or interpersonal psychotherapy at academic medical centers at Pittsburgh, Pennsylvania and Pisa, Italy. The outcomes of primary interest were predictors and moderators time to remission on monotherapy at 12 weeks. Results Participants with higher scores on the need for medical reassurance factor of the PAS-SR had more rapid remission with IPT and those with lower scores on the psychomotor activation factor of the MOODS-SR experienced more rapid remission with SSRI. Nonspecific predictors of longer time to remission with monotherapy included several panic spectrum and mood spectrum factors and the social phobia spectrum total score. Higher baseline HRSD-17 and-25, and Work and Social Adjustment Scale scores also predicted longer time to remission, while being married predicted shorter time to remission. Conclusions This exploratory study identified several nonspecific predictors, but few moderators of psychotherapy vs. pharmacotherapy outcome. It offers useful indicators of the characteristics of patients that are generally difficult to treat, but only limited guidance as to who benefits from IPT versus SSRI pharmacotherapy.

Objective The purpose of this study was to characterize escitalopram population pharmacokinetics (PK)in patients treated for major depression in a cross-national, U.S.-Italian clinical trial. Methods Data from the two sites participating in this trial, conducted at Pittsburgh (USA) and Pisa (Italy) were utilized. Patients received 5, 10, 15, or 20 mg of escitalopram daily for a minimum of 32 weeks. Nonlinear mixed-effects modeling (NONMEM) was used to model the PK characteristics of escitalopram. One and two compartment models with various random effect implementations were evaluated during model development. Objective function values (OFV) and goodness of fit plots were used as model selection criteria. CYP2C19 genotype, age, weight, BMI, sex, race, and clinical site were evaluated as possible covariates. Results 320 plasma concentrations from 105 Pittsburgh patients and 153 plasma concentrations from 67 Pisa patients were available for the PK model development. A one-compartmental model with linear elimination and proportional error best described the data. Apparent clearance (CL/F) and volume of distribution (V/F) for escitalopram without including any covariates in the patient population were 23.5 L/h and 884 L , respectively. CYP2C19 genotype, weight and age had a significant effect on CL/F, and patient BMI affected estimated V/F. Pisa, Italy patients had significantly lower clearances than Pittsburgh patients that disappeared after controlling for patient CYP2C19 genotype, age, and weight. Post-processed individual empirical Bayes estimates on clearance for the 172 patients show that patients without allele CYP2C19*2 or *3 (n=82) cleared escitalopram 33.7% faster than patients with heterogeneous or homogeneous *2 or *3 (*17/*2, *17/*3, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3,n=46). CL/F significantly decreased with increasing patient age. Patients younger than 30 years (n=45) cleared escitalopram 20.7% and 42.7% faster than patients aged 30-50 years (n=84) and greater than 50 years of age (n=43), respectively. Conclusions CYP2C19 genotype, age, and weight strongly influenced the CL/F of escitalopram. Patients with heterogeneous or homogeneous CYP2C19*2 or *3 genotype had significantly lower clearances than patients with other genotypes. CL/F significantly decreased with either increasing age or decreasing body weight. These variables may affect patient tolerance of this antidepressant and, consistent with the NIH emphasis on personalized treatment, may provide important information in the effort to tailor treatments to patients’ individual needs.

Approximately 40% of patients with bipolar disorder experience mixed episodes, defined as a manic state with depressive features, or manic symptoms in a patient with bipolar depression. Compared with bipolar patients without mixed features, patients with bipolar mixed states generally have more severe symptomatology, more lifetime episodes of illness, worse clinical outcomes and higher rates of comorbidities, and thus present a significant clinical challenge. Most clinical trials have investigated second-generation neuroleptic monotherapy, monotherapy with anticonvulsants or lithium, combination therapy, and electroconvulsive therapy (ECT). Neuroleptic drugs are often used alone or in combination with anticonvulsants or lithium for preventive treatment, and ECT is an effective treatment for mixed manic episodes in situations where medication fails or cannot be used. Common antidepressants have been shown to worsen mania symptoms during mixed episodes without necessarily improving depressive symptoms; thus, they are not recommended during mixed episodes. A greater understanding of pathophysiological processes in bipolar disorder is now required to provide a more accurate diagnosis and new personalised treatment approaches. Targeted, specific treatments developed through a greater understanding of bipolar disorder pathophysiology, capable of affecting the underlying disease processes, could well prove to be more effective, faster acting, and better tolerated than existing therapies, therefore providing better outcomes for individuals affected by bipolar disorder. Until such time as targeted agents are available, second-generation neuroleptics are emerging as the treatment of choice in the management of mixed states in bipolar disorder.

The implementation of a cross-national protocol and the adoption and maintenance of common procedures is possible when investigators are aware of the challenges this may present and are proactive in trying to address them.