Model-Guided Antipsychotic Dose Reduction in Schizophrenia: A Pilot, Single-Blind Randomized Controlled Trial.

PURPOSE/BACKGROUND: Patients with schizophrenia as well as their psychiatrists are hesitant to reduce the antipsychotic dose in fear of relapse. To overcome such dilemmas, we developed models to individually calculate an oral dose that corresponds to a given target dopamine D2 receptor occupancy. METHODS/PROCEDURES: In this pilot, 52-week single-blind randomized controlled trial, 35 clinically stable patients with schizophrenia receiving either risperidone or olanzapine monotherapy were randomly assigned to dose reduction (n = 17) or dose maintenance group (n = 18). In the former group, baseline doses were reduced to the doses corresponding to 65% D2 occupancy (the lower end of therapeutic window) at trough that were calculated from randomly collected plasma concentrations using our models. FINDINGS/RESULTS: In the dose reduction group, doses of risperidone and olanzapine were decreased from 4.2 ± 1.9 to 1.4 ± 0.4 and 12.8 ± 3.9 to 6.7 ± 1.8 mg/d, whereas the doses in the dose maintenance group were 4.3 ± 1.9 and 15.8 ± 4.6 mg/d, respectively. Twelve subjects (70.5%) and 13 subjects (72.2%) in the dose reduction and dose maintenance groups completed the study (P = 0.604), whereas 3 subjects (18.8%) and none dropped out because of clinical worsening in the dose reduction and dose maintenance groups, respectively. There were not significant differences in score changes in Positive and Negative Syndrome Scale between the 2 groups but in Positive subscale scores in the Clinical Global Impression-Schizophrenia (0.4 ± 0.7 in the dose reduction group vs -0.1 ± 0.7 in the dose maintenance group, P = 0.029). IMPLICATIONS/CONCLUSIONS: Although our model-guided dose reduction strategy was found to be comparable with no-dose change in terms of dropout rates, safety issues have to be further examined.

Impact of subjective vs. objective remission status on subjective cognitive impairments in depression.

OBJECTIVE: The impact of subjective vs. objective illness severity on subjective cognitive impairment in patients with depression has not been addressed. METHODS: This study is a post-hoc analysis of our cross-sectional study in Japanese outpatients with depressive disorder (ICD-10) (Ozawa et al., 2017). The participants received assessments with the Japanese version of the Perceived Deficits Questionnaire (J-PDQ), Quick Inventory of Depressive Symptomatology (QIDS), and Montgomery-Asberg Depression Rating Scale (MADRS). First, multiple regression analysis was conducted to examine the effects of demographic and clinical characteristics, including illness severity and medications (e.g., antidepressants and benzodiazepines), on the PDQ total score. Next, we categorized the participants into 4 groups based on the presence/absence of subjective and objective symptom remission (i.e., QIDS total score of ≤5 and MADRS total score of ≤9, respectively), and compared the differences in PDQ total scores between the QIDS- and MADRS-remitted group and the QIDS-non-remitted but MADRS-remitted group. RESULTS: 102 participants were included (45 men; mean ±â€¯SD age, 50.5 ±â€¯14.7 years). Higher QIDS and MADRS total scores were significantly associated with a greater PDQ total score (both p's < 0.001), while other factors did not exhibit any associations. The QIDS-non-remitted but MADRS-remitted group showed a significantly higher PDQ total score than that of the QIDS- and MADRS-remitted group (median 10.0 [8.0-12.0] vs. 3.0 [range: 2.0-4.0], p < 0.001). CONCLUSIONS: These findings suggest that objective remission in the absence of subjective remission may not be adequate to improve subjective cognitive functioning.

Placebo Effects in the Treatment of Noncognitive Symptoms of Alzheimer's Disease: Analysis of the CATIE-AD Data.

OBJECTIVE: To compare symptom trajectories between placebo and active drug responders and to examine whether early placebo improvement would be associated with subsequent placebo response in the treatment of patients with behavioral and psychological symptoms of dementia. METHODS: A post hoc analysis of data from 371 patients with DSM-IV Alzheimer's disease in Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness for Alzheimer's disease (CATIE-AD) (April 2001 to November 2004) was conducted. Patients were randomly assigned to double-blind treatment with olanzapine, quetiapine, risperidone, or placebo. Trajectories of change in Brief Psychiatric Rating Scale (BPRS) total scores were compared between placebo and active drug responders. The predictive power of improvement at week 2 for response at week 8 was investigated, and sensitivity and specificity of incremental 5% cutoff points between 5% and 25% reduction in BPRS total score at week 2 were calculated. RESULTS: There were no significant differences in symptom trajectories between placebo and active drug responders. BPRS score reduction at week 2 was significantly associated with placebo response at week 8 (odds ratio = 1.13; P < .001). Use of a cutoff of 10% showed the highest accuracy of 0.67 (sensitivity, 0.63; specificity, 0.70). CONCLUSIONS: Symptom trajectories of improvement of behavioral and psychological symptoms of dementia follow the same pattern irrespective of treatment. A 10% improvement at week 2 was the most appropriate predictor of subsequent placebo response at week 8, which may indicate utility for the placebo lead-in phase to minimize future trial failures of treatment for noncognitive symptoms of Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00015548.

Resilience and spirituality in patients with depression and their family members: A cross-sectional study.

OBJECTIVE: The degree and quality of resilience in patients with depression have never been investigated in the context of remission status, spirituality/religiosity, and family members' resilience levels, which was addressed in this study. METHODS: This cross-sectional study recruited Japanese outpatients with depressive disorder according to ICD-10 and cohabitant family members who were free from psychiatric diagnoses. Resilience was assessed using the 25-item Resilience Scale (RS). Other assessments included the Montgomery-Asberg Depression Rating Scale (MADRS); the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT) and Kasen et al.'s (2012) scale for spirituality/religiosity; and the Rosenberg Self-Esteem Scale (RSES). RESULTS: One hundred outpatients with depression (mean±SD age, 50.8±14.5years; 44 men; MADRS total score 9.8±9.0) and 36 healthy family members (mean±SD age, 56.5±15.0years; 18 men) were included. Symptom severity, attendance at religious/spiritual services, and self-esteem were significantly associated with RS scores in the patient group. RS total scores were significantly higher in remitted patients compared to non-remitted patients (mean±SD, 112.3±17.1 vs. 84.8±27.7, p<0.001). No correlation was found in RS total scores between patients and their family members (p=0.265), regardless of patients' remission status. CONCLUSIONS: Resilience may be influenced by individual characteristics rather than familial environment; furthermore, self-esteem or spirituality/religiosity may represent reinforcing elements. While caution is necessary in extrapolating these findings to other patient populations, our results suggest that resilience may be considered a state marker in depression.

Melancholic and reactive depression: a reappraisal of old categories.

BACKGROUND: The dominant diagnostic model of the classification of depression today is unitarian; however, since Kurt Schneider (1920) introduced the concept of endogenous depression and reactive depression, the binary model has still often been used on a clinical basis. Notwithstanding this, to our knowledge, there have been no collective data on how psychiatrists differentiate these two conditions. We therefore conducted a survey to examine how psychiatrists in Japan differentiate patients with major depressive disorder who present mainly with melancholic features and those with reactive features. METHODS: Three case scenarios of melancholic and reactive depression, and one-in-between were prepared. These cases were designed to present with at least 5 symptoms listed in the DSM-IV-TR with severity being mild. We have sent the questionnaires regarding treatment options and diagnosis for those three cases on a 7-point Likert scale (1 = "not appropriate", 4 = "cannot tell", and 7 = "appropriate"). Five hundred and two psychiatrists from over one hundred hospitals and community clinics throughout Japan have participated in this survey. RESULTS: The melancholic case resulted significantly higher than the reactive case on either antidepressants (mean ± SD: 5.9 ± 1.2 vs. 3.6 ± 1.7, p < 0.001), hypnotics (mean ± SD: 5.5 ± 1.1 vs. 5.0 ± 1.3, p < 0.001), and electroconvulsive therapy (mean ± SD: 1.5 ± 0.9 vs. 1.2 ± 0.6, p < 0.001). On the other hand, the reactive case resulted in significantly higher scores compared to the melancholic case and the one- in-between cases in regards to psychotherapy (mean ± SD: 4.9 ± 1.4 vs. 4.3 ± 1.4 vs. 4.7 ± 1.5, p < 0.001, respectively). Scores for informing patients that they suffered from "depression" were significantly higher in the melancholic case, compared to the reactive case (mean ± SD: 4.7 ± 1.7 vs. 2.2 ± 1.4, p < 0.001). CONCLUSIONS: Japanese psychiatrists distinguish between major depressive disorder with melancholic and reactive features, and thus choose different treatment strategies regarding pharmacological treatment and psychotherapy.