A significant percentage of depressive patients do not respond to a first antidepressant treatment, independent of the class of drugs used. or ARI was added to paroxetine in a randomized protocol for 4 weeks. We defined the patients whose scores around the Hamilton Rating Scale for Depressive disorder decreased 50% or more as responders. Results: Two patients dropped out because of adverse effects. Response rates to Li, OLA or ARI augmentation were 4/10 (40%), 3/10 (30%) and 4/10 (40%), respectively. In addition, Li, OLA and ARI did not influence plasma paroxetine concentrations. Conclusions: We concluded that OLA or ARI could be used as alternatives to Li as options for patients who do not respond to paroxetine treatment. 2006]. Recently, adjunctive use of atypical antipsychotic drugs has increased. Lithium (Li) augmentation is the strategy with the most robust evidence for treatment of refractory depressive disorder [Bschor and Bauer, 2006]. A meta-analysis by Nelson and Papakostas (2009) exhibited that the odds ratio for response with antipsychotic augmentation placebo was 1.65. Our own recent study showed that adding a low dose of atypical antipsychotic drug to ongoing treatment with a selective serotonin inhibitor (SSRI) or serotonin noradrenaline reuptake inhibitor (SNRI) brought a rapid improvement within 4 weeks [Yoshimura 2010]. In addition, it significantly increased serum levels of brain-derived neurotrophic factor (BDNF). However, the ongoing first-line antidepressants studied in previous reports varied [Yoshimura 2010]. Therefore, it remains uncertain whether atypical antipsychotic drugs improve symptoms in patients who do not respond to treatment specifically with paroxetine. Moreover, it is still not known which atypical drug produces the best response when added to ongoing paroxetine treatment. The aim of the present Permethrin study was to compare the impact of adding Li, olanzapine (OLA) and aripiprazole (ARI) to paroxetine in patients with MDD. We also measured serum levels of BDNF and plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), a major metabolite of noradrenaline, as well as homovanillic Permethrin acid (HVA), a major metabolite of dopamine, to elucidate their mechanisms. Subjects and methods The study initially enrolled 89 patients who met the Diagnostic and Statistical Manual of Mental Disorders IV Text Revision (DSM-IV-TR) criteria for MDD. There were 39 males and 50 females, ranging in age from 29 to 71 [mean standard deviation (SD), 4614) years. All patients were actually healthy and free of current alcohol or drug abuse, comorbid stress and personality disorders. A total of 48 of 89 patients responded to treatment with paroxetine within 8 weeks. We defined responded as a 50% or more decrease in score around the 17 items of the Hamilton Rating Scale for Depressive disorder (HAMD-17). We defined remission as HAMD-17 scores below 7. The remaining 30 patients were considered nonresponders to paroxetine treatment. These patients were randomly administered Li, ARI or OLA in addition to their ongoing paroxetine treatment. The study protocol was approved by the Ethics Committee of the University of Occupational and Environmental Health [Kitakyushu, Japan). All patients signed informed consent forms after having been informed of the studys purpose. Dosages of antidepressants and atypical antipsychotics varied among patients and were not fixed for ethical reasons. However, doses of antidepressants were not altered during the comedication period. Benzodiazepines were the only hypnotics permitted and their dosages were kept constant throughout the study period. Clinical improvement of patients was evaluated using the HAMD-17 before the start of the study, and weekly after administration of Li or other atypical antipsychotic drugs had begun. Patients whose HAMD-17 scores decreased by 50% within 4 weeks after adding the atypical antipsychotic drug were defined as responders; those whose HAMD-17 scores decreased to 7 or less were defined as remissions; the remainder were defined as nonresponders. Serum BDNF assay All blood samples were taken at 7 a.m., before breakfast and at least 12 hours after the last dose of medication. Samples were drawn before the start of the study (T0), and then at four (T4) and eight weeks (T8) after treatment with paroxetine, sertraline or fluvoxamine. Venous blood (15 ml) was drawn with the patient lying in a supine position after resting overnight. Serum samples were quickly separated in a centrifuge (2000at 4 C. Extraction was performed under a vacuum using Bond-Elut columns (Varian, Palo Alto, CA, USA) prepacked with 100 mg of C18-bonded silica (40 m) in a 1 ml capacity disposable syringe. The columns, which were inserted into a vacuum chamber connected to an aspirator, were prepared by washing with 1 ml methanol followed by 1 ml of water. After the.Plasma paroxetine levels did not change after the addition of Li. options for patients who do not respond to paroxetine treatment. 2006]. Recently, adjunctive use of atypical antipsychotic drugs has increased. Lithium (Li) augmentation is the strategy with the most robust Ptgfr evidence for treatment of refractory depressive disorder [Bschor and Bauer, 2006]. A meta-analysis by Nelson and Papakostas (2009) exhibited that the odds ratio for response with antipsychotic augmentation placebo was 1.65. Our own recent Permethrin study showed that adding a low dose of atypical antipsychotic drug to ongoing treatment with a selective serotonin inhibitor (SSRI) or serotonin noradrenaline reuptake inhibitor (SNRI) brought a rapid improvement within 4 weeks [Yoshimura 2010]. In addition, it significantly increased serum levels of brain-derived neurotrophic factor (BDNF). However, the ongoing first-line antidepressants studied in previous reports varied [Yoshimura 2010]. Therefore, it remains uncertain whether atypical antipsychotic drugs improve symptoms in patients who do not respond to treatment specifically with paroxetine. Moreover, it is still not known which atypical drug produces the best response when added to ongoing paroxetine treatment. The aim of the present study was to compare the impact of adding Li, olanzapine (OLA) and aripiprazole (ARI) to paroxetine in patients with MDD. We also measured serum levels of BDNF and plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), a major metabolite of noradrenaline, as well as homovanillic acid (HVA), a major metabolite Permethrin of dopamine, to elucidate their mechanisms. Subjects and methods The study initially enrolled 89 patients who met the Diagnostic and Statistical Manual of Mental Disorders IV Text Revision (DSM-IV-TR) criteria for MDD. There were 39 males and 50 females, ranging in age from 29 to 71 [mean standard deviation (SD), 4614) years. All patients were actually healthy and free of current alcohol or drug abuse, comorbid stress and personality disorders. A total of 48 of 89 patients responded to treatment with paroxetine within 8 weeks. We defined responded as a 50% or more decrease in score around the 17 items of the Hamilton Rating Scale for Depressive disorder (HAMD-17). We defined remission as HAMD-17 scores below 7. The remaining 30 patients were considered nonresponders to paroxetine treatment. These patients were randomly administered Li, ARI or OLA in addition to their ongoing paroxetine treatment. The study protocol was approved by the Ethics Committee of the University of Occupational and Environmental Health [Kitakyushu, Japan). All patients signed informed consent forms after having been informed of the studys purpose. Dosages of antidepressants and atypical antipsychotics varied among patients and were not fixed for ethical reasons. However, doses of antidepressants were not altered during the comedication period. Benzodiazepines were the only hypnotics permitted and their dosages were kept constant throughout the study period. Clinical improvement of patients was evaluated using the HAMD-17 before the start of the study, and weekly after administration of Li or other atypical antipsychotic drugs had begun. Patients whose HAMD-17 scores decreased by 50% within 4 weeks after adding the atypical antipsychotic drug were defined as responders; those whose HAMD-17 scores decreased to 7 or less were defined as remissions; the remainder were defined as nonresponders. Serum BDNF assay All blood samples were taken at 7 a.m., before breakfast and at least 12 hours after the last dose of medication. Samples were drawn before the start of the study (T0), and then at four (T4) and eight weeks (T8) after treatment with paroxetine, sertraline or fluvoxamine. Venous blood (15 ml) was drawn with the patient lying in a supine position after resting overnight. Serum samples were quickly.
