A Proof-of-Concept Study Evaluating the Phosphodiesterase 10A Inhibitor PF-02545920 in the Adjunctive Treatment of Suboptimally Controlled Symptoms of Schizophrenia.

BACKGROUND: Effective treatments for managing suboptimal clinical responses to current therapy for schizophrenia remain a critical unmet need. Phosphodiesterase 10A (PDE10A) inhibition represents a mechanistically novel approach to the treatment of schizophrenia, with preclinical studies suggesting improvements in partially responsive symptoms could be achieved via adjunctive use of the PDE10A inhibitor PF-02545920. Therefore, the adjunctive safety, tolerability, pharmacokinetics, and efficacy of multiple repeat doses of PF-02545920 were investigated in a phase 1b study and subsequent phase 2 study. METHODS: The phase 1b study randomized 37 adult patients with stable symptomatology and stable antipsychotic regimens within 3 cohorts. Study participants received ascending doses of PF-02545920 or placebo for 10 to 18 days. The phase 2 study randomized 240 outpatients with stable symptomatology but suboptimal response to current antipsychotic regimens 1:1:1 to PF-02545920 5 mg, PF-02545920 15 mg, or placebo every 12 hours for 12 weeks. The primary efficacy end point of the phase 2 study was change in the Positive and Negative Syndrome Scale total score from baseline to week 12, with changes in other clinical assessments as secondary end points. RESULTS: Treatment was well tolerated, and observed PF-02545920 exposures were within the range predicted to be adequate for demonstrating efficacy. However, no significant differences in the prespecified efficacy end points between the 2 PF-02545920 treatment arms and placebo were observed. CONCLUSIONS: Current data and results of a prior monotherapy study in which PF-02545920 failed to differentiate from placebo refute the hypothesis that PDE10A inhibitors have use as antipsychotic agents for schizophrenia.

Safety and pharmacokinetics of lisdexamfetamine dimesylate in adults with clinically stable schizophrenia: a randomized, double-blind, placebo-controlled trial of ascending multiple doses.

To assess the safety and pharmacokinetics of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, this double-blind study enrolled adults with clinically stable schizophrenia who were adherent (≥12 weeks) to antipsychotic pharmacotherapy. The participants received placebo or ascending LDX doses (50, 70, 100, 150, 200, and 250 mg) daily for 5 days at each dose (dose periods, 1-6; days, 1-5). Of the 31 enrolled participants, 27 completed the study (placebo, n = 6; LDX, n = 21). Treatment-emergent adverse events (AEs) were reported by 4 participants receiving placebo and by 23 participants receiving LDX (all doses) with no serious AEs while on active treatment. For all periods, the mean postdose change on day 5 (up to 12 hours postdose) in systolic and diastolic blood pressure and pulse, respectively, ranged from -4.62 to 8.05 mm Hg, -3.67 to 4.43 mm Hg, and -3.57 to 14.43 beats per minute for placebo and -3.83 to 11.25 mm Hg, -1.55 to 5.80 mm Hg, and -0.36 to 21.26 beats per minute for LDX. With ascending LDX dose, the mean (SD) maximum plasma concentration for LDX-derived d-amphetamine ranged from 51.68 (10.28) to 266.27 (56.55) ng/mL. The area under the plasma concentration-time curve for 24 hours ranged from 801.8 (170.2) to 4397.9 (1085.9) ng[BULLET OPERATOR]h/mL. The d-amphetamine maximum plasma concentration and area under the plasma concentration-time curve increased linearly with ascending LDX dose. Antipsychotic agents did not markedly affect d-amphetamine pharmacokinetics. Over a wide range of ascending doses, LDX safety profile in adults with schizophrenia was consistent with previous findings with no unexpected treatment-emergent AEs. Pulse tended to increase with LDX dose; overall, blood pressure did not increase with LDX dose. Consistent with previous studies, pharmacokinetic parameters increased linearly with increasing LDX dose.

The H3 antagonist ABT-288 is tolerated at significantly higher exposures in subjects with schizophrenia than in healthy volunteers.

AIMS: ABT-288 is a potent and selective H3 receptor antagonist with procognitive effects in several preclinical models. In previous studies, 3 mg once daily was the maximal tolerated dose in healthy volunteers. This study characterized the safety, tolerability and pharmacokinetics of ABT-288 in stable subjects with schizophrenia. METHODS: This was a randomized, double-blind, placebo-controlled, dose-escalating study of ABT-288 (10 dose levels, from 1 to 60 mg once daily for 14 days) in stable subjects with schizophrenia treated with an atypical antipsychotic. In each dose group, five to seven and two to three participants were assigned to ABT-288 and placebo, respectively. RESULTS: Of the 67 participants enrolled, nine participants (on ABT-288) were prematurely discontinued, in seven of these due to adverse events. ABT-288 was generally safe and tolerated at doses up to 45 mg once daily. The most common adverse events, in decreasing frequency (from 31 to 5%), were abnormal dreams, headache, insomnia, dizziness, somnolence, dysgeusia, dry mouth, psychotic disorder, parosmia and tachycardia. Adverse events causing early termination were psychotic events (four) and increased creatine phosphokinase, pyrexia and insomnia (one each). The half-life of ABT-288 ranged from 28 to 51 h, and steady state was achieved by day 12 of dosing. At comparable multiple doses, ABT-288 exposure in subjects with schizophrenia was 45% lower than that previously observed in healthy subjects. At trough, ABT-288 cerebrospinal fluid concentrations were 40% of the total plasma concentrations. CONCLUSIONS: ABT-288 was tolerated at a 15-fold higher dose and 12-fold higher exposures in subjects with schizophrenia than previously observed in healthy volunteers. The greater ABT-288 tolerability was not due to limited brain uptake.

Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder.

OBJECTIVE: The objective of this study was to explore the efficacy of combination therapy with citalopram plus omega-3 fatty acids versus citalopram plus placebo (olive oil) in the initial treatment of individuals with major depressive disorder (MDD). We hypothesized that combination therapy would lead not only to greater efficacy but also to a more rapid onset of therapeutic response. METHODS: Forty-two subjects participated in this 9-week randomized, masked, placebo-controlled study of combination therapy (two 1 g capsules containing a blend of 900 mg of eicosapentaenoic acid, 200 mg of and docosahexaenoic acid, and 100 mg of other omega-3 fatty acids twice daily plus citalopram) versus monotherapy (two 1 g capsules of olive oil per day plus citalopram) treatment of MDD. RESULTS: The combination therapy demonstrated significantly greater improvement in Hamilton Depression Rating scale scores over time (F = 7.32; df 1,177; P = 0.008) beginning at week 4 (t = -2.48; df 177; P = 0.014). CONCLUSIONS: Combination therapy was more effective than monotherapy in decreasing signs and symptoms of MDD during the 8 weeks of active treatment; however, combination therapy did not seem to enhance the speed of the initial antidepressant response. These findings suggest that there may be an advantage to combining omega-3 fatty acids with a selective serotonin uptake inhibitor in the initial treatment of individuals with MDD. A larger definitive study is warranted.

Pharmacokinetics of ASP4345 from Single Ascending-Dose and Multiple Ascending-Dose Phase I Studies.

BACKGROUND: Cognitive impairment is a core feature of schizophrenia. While first- and second-generation antipsychotic drugs treat psychotic exacerbations, no treatment is approved for the cognitive dysfunction. We have identified ASP4345, a positive allosteric modulator of the dopamine type 1 (D1) receptor that selectively binds to, and enhances the activity of, D1 receptors. ASP4345 has the potential to be an effective and well-tolerated treatment option for cognitive impairment associated with schizophrenia. OBJECTIVE: The objective of this study was to determine the pharmacokinetics of ASP4345 in two phase I single ascending-dose and multiple ascending-dose studies. METHODS: Both phase I studies were randomized, double blind, and placebo controlled. The single dose-ascending study assessed pharmacokinetics of single oral doses of 3-900 mg of ASP4345 or placebo in the fasted state in healthy adult volunteers. This study also assessed cerebrospinal fluid pharmacokinetics, as well as the effects of food on pharmacokinetic parameters. The multiple ascending-dose study (NCT02720263) assessed the pharmacokinetics of multiple oral doses of 3-150 mg of ASP4345 in patients with schizophrenia or schizoaffective disorder receiving stable antipsychotic drug treatment. The pharmacokinetic data from both studies were summarized using descriptive statistics. RESULTS: The plasma concentration-time profile in both studies showed a rapid increase in concentrations of ASP4345. The median time to maximum concentration range was 1.00-2.26 h in the single ascending-dose study in the fasted state and 1.25-3.02 h in the multiple ascending-dose study at steady state. There were less than dose-proportional increases in maximum concentration and area under the curve in the single ascending-dose study, where doses had a range from 3 to 900 mg, and in the multiple ascending-dose study in patients with stabilized schizophrenia or schizoaffective disorder, where doses had a range from 3 to 150 mg. The mean terminal elimination half-life was dose independent and had a range from 9.12 to 14.3 h in the single ascending-dose study and from 11.1 to 26.8 h in the multiple ascending-dose study. Additionally, in the single ascending-dose study, absorption of 300 mg of ASP4345 was slightly delayed when administered in the fed state compared with the fasted state; median time to maximum concentration was 1.5 h under the fasting state and 4.0 h under fed states. All other pharmacokinetic parameters were comparable for both conditions. ASP4345 appeared in the cerebrospinal fluid with some delay; time to maximum concentration range was from 2.48 to 7.98 h in cerebrospinal fluid compared with 0.75 to 1.03 h in plasma (median cerebrospinal fluid/plasma = 0.188). The ratio of cerebrospinal fluid to total plasma for area under the curve from 0 to 24 h (0.157-0.573%) and maximum concentration (0.0899-0.311%) and the ratio of cerebrospinal fluid to unbound plasma for maximum concentration (25.0-86.4%) confirm the distribution of ASP4345 into the brain. CONCLUSIONS: The pharmacokinetics of ASP4345 suggest that single daily dosing is appropriate for ASP4345. Furthermore, the concentration of ASP4345 in cerebrospinal fluid compared to free drug concentrations in plasma provides evidence of penetration of ASP4345 into the brain.

Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D1 receptor positive allosteric modulator in patients with schizophrenia.

ASP4345, a novel dopamine D1 receptor positive allosteric modulator, is being evaluated for the treatment of cognitive impairment associated with schizophrenia (CIAS). This phase 1 multiple ascending-dose study (NCT02720263) assessed the safety, tolerability, and pharmacodynamics of ASP4345 in patients with schizophrenia/schizoaffective disorder. Pharmacodynamic assessments were Cogstate cognitive tests and electrophysiological biomarkers, including gamma-band power and phase synchronization in response to 40-Hz auditory steady-state stimulation, as well as mismatch negativity (MMN) and P3a event-related potentials. The sample size determination was based on standard practice in assessing safety and tolerability of a new chemical entity. Data were summarized by conversion of this data into effect sizes using descriptive and inferential statistics. A total of 36 randomized patients received ASP4345 (3, 15, 50, and 150 mg; n = 9 each dose) and 12 patients received placebo. Patients in the ASP4345 group experienced 73 treatment-emergent adverse events (TEAEs) and 34 TEAEs were reported for the placebo group. The most common TEAEs were headache and somnolence and nearly all TEAEs were mild in severity. No changes in mood or self-reports of suicidal ideation/behavior were observed. Improvements in performance on cognitive tests were noted, which suggests a potential improvement in psychomotor function and visual attention. Furthermore, positive changes in neurophysiological biomarkers (auditory steady-state response [ASSR] and MMN) suggest improvement in information processing. The findings need to be confirmed in studies with a larger patient population. Nonetheless, the trends in safety and pharmacodynamic data support further clinical development of ASP4345 for the treatment of CIAS.

Proof-of-Mechanism Study of the Phosphodiesterase 10 Inhibitor RG7203 in Patients With Schizophrenia and Negative Symptoms.

Background: Reduced activation of dopamine D1 receptor signaling may be implicated in reward functioning as a potential driver of negative symptoms in schizophrenia. Phosphodiesterase 10A (PDE10A), an enzyme that is highly expressed in the striatum, modulates both dopamine D2- and D1-dependent signaling. Methods: We assessed whether augmentation of D1 signaling by the PDE10 inhibitor RG7203 enhances imaging and behavioral markers of reward functions in patients with schizophrenia and negative symptoms. In a 3-period, double-blind, crossover study, we investigated the effects of RG7203 (5 mg and 15 mg doses) and placebo as adjunctive treatment to stable background antipsychotic treatment in patients with chronic schizophrenia with moderate levels of negative symptoms. Effects on reward functioning and reward-based effortful behavior were evaluated using the monetary incentive delay task during functional magnetic resonance imaging and the effort-cost-benefit and working memory reinforcement learning tasks. Results: Patients (N = 33; 30 male, mean age ± SD 36.6 ± 7.0 years; Positive and Negative Syndrome Scale negative symptom factor score 23.0 ± 3.5 at screening) were assessed at three study centers in the United States; 24 patients completed the study. RG7203 at 5 mg significantly increased reward expectation-related activity in the monetary incentive delay task, but in the context of significantly decreased overall activity across all task conditions. Conclusions: In contrast to our expectations, RG7203 significantly worsened reward-based effortful behavior and indices of reward learning. The results do not support the utility of RG7203 as adjunctive treatment for negative symptoms in patients with schizophrenia.

A Randomized Multiple Dose Pharmacokinetic Study of a Novel PDE10A Inhibitor TAK-063 in Subjects with Stable Schizophrenia and Japanese Subjects and Modeling of Exposure Relationships to Adverse Events.

BACKGROUND: Phosphodiesterase 10A (PDE10A) is selectively expressed in medium spiny neurons of the striatum. TAK-063 is a selective inhibitor of PDE10A in clinical development for the treatment of schizophrenia. OBJECTIVES: Safety, tolerability, and pharmacokinetics (PK) of TAK-063 were evaluated following multiple rising oral doses, and PK/adverse event (AE) models were developed to characterize the relationship between TAK-063 exposure and incidence of specific AEs. METHODS: Healthy Japanese subjects (HJS) aged 20-55 years and subjects with stable schizophrenia (SSS) aged 18-55 years were enrolled and randomized to either TAK-063 or placebo. Study medication was administered as a tablet once daily (at night) with food over a 7-day period. RESULTS: TAK-063 and placebo groups consisted of 62 and 15 subjects, respectively. A majority of subjects (71 of 77) completed the study. AEs were mostly of mild or moderate severity, and no deaths were reported. The most common AE was somnolence. For equivalent doses, the rate of extrapyramidal syndromes (EPS) was higher in SSS than in HJS. PK parameters were comparable between HJS and SSS at equivalent doses. The incidence of somnolence and EPS symptoms increased with exposure, and this was described with the PK/AE model. A maximum tolerated dose was not determined. CONCLUSIONS: Multiple doses of TAK-063 were safe and well tolerated. PK/AE models characterized the incidence of somnolence and EPS with increasing TAK-063 exposure, and simulations suggested that a once-daily dose range of up to 30 mg would be suitable for future studies. CLINICALTRIALS. GOV IDENTIFIER: NCT01879722.

AZD8529, a positive allosteric modulator at the mGluR2 receptor, does not improve symptoms in schizophrenia: A proof of principle study.

INTRODUCTION: Activation of metabotropic glutamate (mGluR2/3) receptors has been proposed as an alternative mechanism to dopaminergic-based antipsychotics to correct glutamatergic deficits hypothesized to underlie schizophrenia symptoms. This study investigates the efficacy and safety of AZD8529, a selective positive allosteric modulator (PAM) at the mGlu2 receptor, in symptomatic patients with schizophrenia. METHODS: Patients were randomized to receive AZD8529 40 mg, risperidone 4 mg, or placebo as monotherapy. Treatment lasted for 28 days, and clinical efficacy was assessed using Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) scores. RESULTS: There were no significant differences between patients treated with AZD8529 versus placebo in change from baseline to endpoint in PANSS total, negative and positive symptom subscale, or CGI-S scores. In contrast, risperidone demonstrated significant efficacy relative to placebo. CONCLUSION: These results do not support a role for the mGluR-2 PAM AZD8529 as an antipsychotic and indicate that positive modulation of mGluR type 2 receptors alone is not sufficient for antipsychotic effects in acutely ill schizophrenia patients.

Effect of bupropion on nocturnal urinary free cortisol and its association with antidepressant response.

The study examined the relationship between pre-treatment nocturnal hypothalamic-pituitary-adrenal (HPA) activity, as reflected by nocturnal urinary free cortisol (NUFC) response to a single-dose of sustained-release bupropion, and the antidepressant effect of the drug. NUFC changes in response to treatment with bupropion also were assessed. NUFC was measured in 20 patients with unipolar major depressive disorder before and after initiating treatment with sustained-release bupropion. Prior to treatment, subjects were studied on two separate sessions, one week apart. On the morning of each session, the participants received bupropion (150 mg, PO) or placebo using a randomized, double-blind procedure. Following the second session, subjects then received open-label treatment with bupropion for 8 weeks. NUFC sampling was repeated at the end of treatment. There was a significant interaction between NUFC concentration in response to single-dose bupropion and its antidepressant effect. Treatment non-responders showed a significant increase in NUFC in response to a single-dose of bupropion, whereas responders showed no such change. In addition, the NUFC response to bupropion challenge correlated significantly with the change in depression ratings as a result of treatment. In contrast to many other antidepressants, treatment with bupropion for 8 weeks did not reduce HPA activity in either responders or non-responders. These findings suggest that the NUFC response to a test-dose of bupropion might be helpful in predicting its antidepressant effect. One possible mechanism for the association between the NUFC response to acute bupropion challenge and antidepressant efficacy might be linked through dopaminergic and/or noradrenergic mechanisms.

Use of translational pharmacodynamic biomarkers in early-phase clinical studies for schizophrenia.

Schizophrenia is a severe mental disorder characterized by cognitive deficits, and positive and negative symptoms. The development of effective pharmacological compounds for the treatment of schizophrenia has proven challenging and costly, with many compounds failing during clinical trials. Many failures occur due to disease heterogeneity and lack of predictive preclinical models and biomarkers that readily translate to humans during early characterization of novel antipsychotic compounds. Traditional early-phase trials consist of single- or multiple-dose designs aimed at determining the safety and tolerability of an investigational compound in healthy volunteers. However, by incorporating a translational approach employing methodologies derived from preclinical studies, such as EEG measures and imaging, into the traditional Phase I program, critical information regarding a compound's dose-response effects on pharmacodynamic biomarkers can be acquired. Furthermore, combined with the use of patients with stable schizophrenia in early-phase clinical trials, significant 'de-risking' and more confident 'go/no-go' decisions are possible.

Open-label, randomized, parallel-group controlled clinical trial of massage for treatment of depression in HIV-infected subjects.

OBJECTIVES: The study objectives were to determine whether massage therapy reduces symptoms of depression in subjects with human immunodeficiency virus (HIV) disease. DESIGN: Subjects were randomized non-blinded into one of three parallel groups to receive Swedish massage or to one of two control groups, touch or no intervention for eight weeks. SETTINGS/LOCATION: The study was conducted at the Department of Psychiatry and Behavioral Neurosciences at Cedars-Sinai Medical Center in Los Angeles, California, which provided primary clinical care in an institutional setting. SUBJECTS: Study inclusion required being at least 16 years of age, HIV-seropositive, with a diagnosis of major depressive disorder. Subjects had to be on a stable neuropsychiatric, analgesic, and antiretroviral regimen for >30 days with no plans to modify therapy for the duration of the study. Approximately 40% of the subjects were currently taking antidepressants. All subjects were medically stable. Fifty-four (54) subjects were randomized, 50 completed at least 1 week (intent-to-treat; ITT), and 37 completed the study (completers). INTERVENTIONS: Swedish massage and touch subjects visited the massage therapist for 1 hour twice per week. The touch group had a massage therapist place both hands on the subject with slight pressure, but no massage, in a uniform distribution in the same pattern used for the massage subjects. OUTCOME MEASURES: The primary outcome measure was the Hamilton Rating Scale for Depression score, with the secondary outcome measure being the Beck Depression Inventory. RESULTS: For both the ITT and completers analyses, massage significantly reduced the severity of depression beginning at week 4 (p ≤ 0.04) and continuing at weeks 6 (p ≤ 0.03) and 8 (p ≤ 0.005) compared to no intervention and/or touch. CONCLUSIONS: The results indicate that massage therapy can reduce symptoms of depression in subjects with HIV disease. The durability of the response, optimal "dose" of massage, and mechanisms by which massage exerts its antidepressant effects remain to be determined.

Response to citalopram is not associated with SLC6A4 genotype in African-Americans and Caucasians with major depression.

AIMS: Ethnic differences in genotype frequency provide a natural condition for assessing the contribution of gene variations to the causes and treatments of disease. Accordingly, the purpose of this study was to determine whether ethnic variations in allele frequencies of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) of the SLC6A4 gene were related to the response to the treatment of depression. MAIN METHODS: African-Americans (n=101) and Caucasians (n=100) with major depressive disorder were treated with the antidepressant citalopram (20-60mg/day) for 8weeks. Genotyping for the long (L) and short (s) alleles (LL, Ls, and ss) of the SLC6A4 gene was performed and the association between genotype and treatment response was assessed. KEY FINDINGS: Subjects in both ethnic groups showed a significant reduction in depression scores over time (p<.0001). However, in spite of a significantly greater frequency of the L allele in African-Americans as compared to Caucasians, a comparable clinical response between the two groups was found with 5-HTTLPR polymorphism not significantly associated with clinical response in either ethnic group. SIGNIFICANCE: The results are consistent with a previous finding and in accord with most of the results obtained in Caucasian subjects that SLC6A4 genotype is not related, at least by itself, to a response to treatment in either ethnic group to any clinically significant degree.

Maximum tolerated dose evaluation of the AMPA modulator Org 26576 in healthy volunteers and depressed patients: a summary and method analysis of bridging research in support of phase II dose selection.

BACKGROUND: A key challenge to dose selection in early central nervous system (CNS) clinical drug development is that patient tolerability profiles often differ from those of healthy volunteers (HVs), yet HVs are the modal population for determining doses to be investigated in phase II trials. Without clear tolerability data from the target patient population, first efficacy trials may include doses that are either too high or too low, creating undue risk for study participants and the development program overall. Bridging trials address this challenge by carefully investigating safety and tolerability in the target population prior to full-scale proof-of-concept trials. OBJECTIVE: Org 26576 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor positive allosteric modulator that acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. In preparation for phase II efficacy trials in major depressive disorder (MDD), two separate phase I trials were conducted to evaluate safety, tolerability, and pharmacokinetics in HVs and in the target patient population. METHODS: Both trials were randomized and placebo controlled, and included multiple rising-dose cohorts (HV range 100-400 mg bid; MDD range 100-600 mg bid). HVs (n = 36) and patients with MDD (n = 54) were dosed under similarly controlled conditions in an inpatient facility, HVs for up to 14 days and MDD patients for up to 28 days. Safety, tolerability, and pharmacokinetics were assessed frequently. RESULTS: Despite comparable pharmacokinetic profiles, the maximum tolerated dose (MTD) in depressed patients was 450 mg bid, twice the MTD established in HVs. No clinically relevant safety issues associated with Org 26576 were noted. CONCLUSION: This article presents safety, tolerability, and pharmacokinetic data from two different populations examined under similar dosing conditions. The important implications of such bridging work in phase II dose selection are discussed, as are study design and data interpretation challenges.

Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial.

Org 26576 acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. The aim of this Phase 1b study (N=54) was to explore safety, tolerability, pharmacokinetics, and pharmacodynamics of Org 26576 in depressed patients. Part I (N=24) evaluated the maximum tolerated dose (MTD) and optimal titration schedule in a multiple rising dose paradigm (range 100 mg BID to 600 mg BID); Part II (N=30) utilized a parallel groups design (100 mg BID, 400 mg BID, placebo) to examine all endpoints over a 28-day dosing period. Based on the number of moderate intensity adverse events reported at the 600 mg BID dose level, the MTD established in Part I was 450 mg BID. Symptomatic improvement as measured by the Montgomery-Asberg Depression Rating Scale was numerically greater in the Org 26576 groups than in the placebo group in both study parts. In Part II, the 400 mg BID dose was associated with improvements in executive functioning and speed of processing cognitive tests. Org 26576 was also associated with growth hormone increases and cortisol decreases at the end of treatment but did not influence prolactin or brain-derived neurotrophic factor. The quantitative electroencephalogram index Antidepressant Treatment Response at Week 1 was able to significantly predict symptomatic response at endpoint in the active treatment group, as was early improvement in social acuity. Overall, Org 26576 demonstrated good tolerability and pharmacokinetic properties in depressed patients, and pharmacodynamic endpoints suggested that it may show promise in future well-controlled, adequately powered proof of concept trials.

Effect of treatment with bupropion on EEG sleep: relationship to antidepressant response.

The objective of this study was to assess whether treatment with sustained-release bupropion (Wellbutrin-SR) produces alterations in electroencephalographic (EEG) sleep that are associated with clinical response to the drug. EEG sleep was measured in 20 patients with unipolar major depressive disorder before and after treatment with sustained-release bupropion. Each EEG sleep session consisted of two consecutive nights. Treatment with bupropion lasted for 8 wk. Compared to EEG sleep measures at baseline, treatment with bupropion significantly lengthened REM latency, increased REM activity and density during the first REM period, and increased total REM density. Differential response to treatment was associated with changes in REM activity and density, but not with REM latency. However, in contrast to many other antidepressants, REM sleep was not suppressed.