Network meta-analysis of biologic treatments for psoriasis using absolute Psoriasis Area and Severity Index values ≤1, 2, 3 or 5 derived from a statistical conversion method.

BACKGROUND: In practice, the goal of treatment for patients with psoriasis is to achieve almost clear or clear skin and maintain disease control, regardless of baseline disease severity. However, identifying absolute Psoriasis Area and Severity Index (PASI) values for new treatment goals is challenging, as most clinical trials report relative PASI 50, 75, 90 or 100 improvements but rarely absolute PASI values achieved. OBJECTIVE: Our objective was to illustrate a statistical conversion method that was developed to derive absolute PASI values from available clinical trial data on relative PASI improvements. The results of network meta-analyses (NMAs) based on these derived data were then compared with those of NMAs based on the corresponding relative PASI improvement data for selected biologics for moderate-to-severe psoriasis. METHODS: The PASI statistical conversion method was applied to relative PASI improvement data for 11 biologic treatment regimens and placebo at 12 weeks using data from 50 published studies. The respective proportions of patients reaching absolute PASI values ≤1, 2, 3 or 5 were then calculated. Frequentist NMAs (Rücker method) were subsequently used to compare efficacy results across relative and absolute PASI data. RESULTS: The ranking of included treatment regimens for patients achieving absolute PASI 0 to 8 was aligned with results for relative PASI scores (from 100 to 60) at end of induction therapy. Across the range of PASI scores considered, the most effective treatment regimens based on both absolute and relative PASI NMAs were brodalumab 210 mg every 2 weeks and ixekizumab 80 mg every 2 weeks, followed by guselkumab 100 mg every 8 weeks and risankizumab 150 mg every 12 weeks. CONCLUSION: Data generated using this mathematical model will be useful to inform ongoing scientific discussions on treatment goals in the absence of primary absolute PASI data for all available treatments for moderate-to-severe plaque psoriasis.

A 24-week multicentre, randomized, open-label, parallel-group study comparing the efficacy and safety of ixekizumab vs. fumaric acid esters and methotrexate in patients with moderate-to-severe plaque psoriasis naive to systemic treatment.

BACKGROUND: Interleukin-17 antagonists have received a first-line label for moderate-to-severe plaque psoriasis. OBJECTIVES: We conducted the first head-to-head trial between the two most commonly used first-line therapies in Germany, fumaric acid esters (FAEs) and methotrexate, and the interleukin-17A antagonist, ixekizumab. METHODS: Systemic-naive patients were randomized in this parallel-group, active-comparator, open-label, rater-blinded trial (each group n = 54). The primary outcome was the proportion of patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at 24 weeks. Key secondary outcomes included 24-week PASI 90 and 100, static Physician's Global Assessment (sPGA) score of 0 or 1, and Dermatology Life Quality Index (DLQI) score of 0 or 1. Safety events at week 24 were analysed using Fisher's exact test. Missing data were imputed using nonresponder imputation. The trial was registered at ClinicalTrials.gov (NCT02634801) and EudraCT (2015-002649-69). RESULTS: At week 24, more ixekizumab-treated patients achieved PASI 75 [91% vs. 22% FAEs (P < 0·001) and 70% methotrexate (P = 0·014)], PASI 90 [80% vs. 9% FAEs (P < 0·001) and 39% methotrexate (P < 0·001)] and PASI 100 [41% vs. 4% FAEs (P < 0·001) and 13% methotrexate (P = 0·0041)], as well as sPGA (0,1) and DLQI (0,1). CONCLUSIONS: Ixekizumab was superior in inducing PASI 75/90/100, sPGA (0,1) and DLQI (0,1) responses at week 24 compared with methotrexate and FAEs. Safety profiles for all treatments were consistent with prior studies.

Worldwide-Schizophrenia Outpatient Health Outcomes (W-SOHO): baseline characteristics of pan-regional observational data from more than 17,000 patients.

OBJECTIVE: To describe the Worldwide-Schizophrenia Outpatient Health Outcomes (W-SOHO) patient population at study entry, focusing on illness burden and prescribing practices across regions. METHODS: The SOHO study was a 3-year, prospective, observational study designed to assess costs and outcomes associated with antipsychotic use in outpatients initiating or changing antipsychotic (with an emphasis on olanzapine compared with other antipsychotics). SOHO was conducted in 10 European countries and 27 other countries as Intercontinental SOHO (IC-SOHO). Data from all countries have been pooled to produce the W-SOHO dataset. MAIN OUTCOMES MEASURES: Clinical Global Impression-Schizophrenia (CGI-SCH) severity scores, psychotropic medication use, adverse events, social interaction, housing and employment status, self-perceived health state (EuroQoL EQ-5D scale and Visual Analogue Scale, EQ-VAS), and reasons for initiation/change of antipsychotic. RESULTS: The W-SOHO database comprises 17,384 patients from six regions; East Asia (n = 1223), Central and Eastern Europe (n = 2175), Northern Europe (n = 4291), Southern Europe (n = 5788), Latin America (n = 2566), North Africa and the Middle East (n = 1341). Overall, patients were 38 +/- 13 years old (mean +/- SD), moderately ill (mean CGI-SCH overall score of 4.4 +/- 1.0) with a median duration of illness of 7 years (interquartile range 1-16 years); 43% were female, 10% were receiving antipsychotic medication for the first time. Adverse events were prevalent across all regions; on average, 50% (range 41-59%) of patients taking antipsychotics exhibited extrapyramidal symptoms at baseline, and 62% (34-67%) of patients reported sexual dysfunction in the previous month. On average, only 19% (16-23%) of patients were in paid employment and as many as 69% were living in dependent housing. CONCLUSIONS: Despite inherent diversity in these patients and the health care systems supporting them, there are striking cross-regional similarities in baseline characteristics for most measures. Not all countries are represented; regional comparisons may not be valid outside of the countries studied.

Association between painful physical symptoms and clinical outcomes in East Asian patients with major depressive disorder: a 3-month prospective observational study.

AIMS: Reports from non-Asian populations indicate that painful physical symptoms (PPS) are associated with poorer clinical and functional outcomes in major depressive disorder (MDD). The purpose of this study is to report comparative changes in disease severity, treatment patterns and quality of life observed in East Asian patients with MDD, with and without PPS, as assessed prospectively over a 3-month observation period. METHODS: This observational study enrolled 909 patients with MDD in psychiatric care settings in China, Hong Kong, Korea, Malaysia, Singapore and Taiwan. Patients were classified as PPS positive (PPS+) or negative (PPS-) based on mean modified Somatic Symptom Inventory scores of >or= 2 or < 2 respectively. The Clinical Global Impression of Severity (CGI-S) and 17-item Hamilton Depression Rating Scale (HAMD(17)) determined depression severity; a visual analogue scale (VAS) determined pain severity; and the EuroQoL (EQ-5D) assessed well-being after 3 months observation. RESULTS: Of the 909 enrollees, 355/471 (75.4%) of PPS+ patients and 363/438 (82.9%) of PPS- patients completed the study (p = 0.006). PPS+ patients improved less than PPS- patients on depression, pain and quality of life measures during the study (HAMD(17) p < 0.001, CGI-S p < 0.001, VAS p = 0.008 and EQ-5D p = 0.004). Fewer PPS+ patients (46.5%) achieved remission compared with PPS- patients (69.4%, p < 0.001). CONCLUSION: As the presence of PPS is associated with poorer outcomes in East Asian MDD patients, clinical management should aim to address both the mental and PPS associated with MDD.

Olanzapine vs haloperidol in geriatric schizophrenia: analysis of data from a double-blind controlled trial.

OBJECTIVES: To compare the six-week clinical response and safety profile of schizophrenia patients, age > or =60 years, receiving olanzapine (OLZ) vs haloperidol (HAL) in a double blind, randomized trial. METHODS: Double-blind data on patients age > or =60 randomized to 5 mg/d OLZ (n=83) or 5 mg/d HAL (n=34) (Week 1) then flexibly dosed to 5-20 mg/d over six weeks, with a 48-week extension for responders, were analyzed post-hoc. Efficacy indices included the PANSS Total and PANSS Psychosis Core Total (PPCT). Safety measures included the Simpson-Angus Scale (SAS), Barnes Akathisia Scale (BAS), Abnormal Involuntary Movement Scale (AIMS), treatment-emergent adverse events, and laboratory values. Mixed model, repeated measures (MMRM) analyses were applied to all continuous data measured at each visit. Continuous data recorded only at phase completion or termination were analyzed with a fixed effect last observation carried forward (LOCF) model. Frequencies of categorical response data were analyzed using Fisher's exact methods. Differences were tested for significance at Week 6 using a two-sided alpha value of 0.05. RESULTS: HAL group (n=34; age range 60-80) received a mean modal dose 9.4 mg/d while OLZ group (n=83; age range 60-86) received a mean modal dose 11.9 mg/d. At Week 6, OLZ was superior to HAL on both the PANSS Total (p=0.015) and PPCT (p=0.043). Considering safety, OLZ was superior to HAL for the SAS and BAS (p<0.001; p<0.001). No spontaneous adverse event occurred more frequently with OLZ than with HAL. In patients never receiving adjunct anticholinergic therapy, no significant differences were present for anticholinergic-like side effects including blurred vision, dry mouth, constipation, or urinary difficulties. CONCLUSIONS: In elderly schizophrenia patients, olanzapine was more efficacious and better tolerated for extrapyramidal signs than was haloperidol. Olanzapine was equivalent to haloperidol for anticholinergic-like side effects when corrected for anticholingergic agents.

A current review of olanzapine's safety in the geriatric patient: from pre-clinical pharmacology to clinical data.

OBJECTIVE: Olanzapine (OLZ) is unique among currently available antipsychotic medications in its antagonism of a range of receptor systems including dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Olanzapine's mechanistic complexity provides a broad efficacy profile in patients with schizophrenia and acute, pure or mixed mania. Patients experience symptomatic relief of mania, anxiety, hallucinations, delusions, and agitation/aggression and reduced depressive, negative, and some cognitive symptoms. This paper will review the safety profile of OLZ, focusing on the elderly, where data are available. METHOD: Preclinical and clinical studies of OLZ are reviewed, with emphasis on its possible effects on the cholinergic system and the histamine H(1) receptor. Weight change and related metabolic considerations, cardiac and cardiovascular safety, and motor function during treatment with OLZ are also reviewed. RESULTS AND CONCLUSION: In vitro receptor characterization methods, when done using physiologically relevant conditions allow accurate prediction of the relatively low rate of anticholinergic-like adverse events, extrapyramidal symptoms, and cardiovascular adverse events during treatment with OLZ. Currently available clinical data suggest olanzapine is predictably safe in treating adult patients of any age with schizophrenia and acute bipolar mania, as well as in treatment of patients with some types of neurodegenerative disorders.

Gender differences in the efficacy of fluoxetine and maprotiline in depressed patients: a double-blind trial of antidepressants with serotonergic or norepinephrinergic reuptake inhibition profile.

BACKGROUND: Depression has emerged as a contrastive area of gender differences in psychiatry, as epidemiological data has consistently shown depression is twice as common in women as men. The pharmacodynamic effect of antidepressants may also show gender differences, as suggested by reports of better response of young women to non-tricyclic antidepressants. METHODS: The antidepressive effect of an SSRI (fluoxetine) and a tetracyclic antidepressant with selective norepinephrine reuptake inhibitory effect (maprotiline) was compared in a 6-week, double-blind trial of 105 depressed patients. RESULTS: No significant difference was observed in the change of HAMD17 total score from baseline to week 6 between fluoxetine- and maprotiline-treated patients. A significant difference was observed in females (fluoxetine, -17.8; maprotiline, -13.9; P=0.017) between treatment groups, but not in males. Amongst females, the difference was significant in women aged <44 years (fluoxetine, -18.4; maprotiline, -12.9; P=0.023) but not > or =44 years. CONCLUSIONS: Females in their reproductive period are more responsive to SSRI (fluoxetine) than norepinephrinergic tetracyclic antidepressant (maprotiline) treatment. Normal cyclical ovulation, and estrogen release may have a clinically relevant pharmacodynamic interaction with serotonergic antidepressants.

An efficacy analysis of olanzapine treatment data in schizophrenia patients with catatonic signs and symptoms.

Thirty-five patients suffering from schizophrenia, as diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were preselected from 7 clinical trials according to a priori criteria of catatonic signs and symptoms based on 3 Positive and Negative Syndrome Scale (PANSS) items: scores for PANSS item 19 (mannerism and posturing) and either item 4 (excitement) or item 21 (motor retardation) had to exceed or equal 4 at baseline. This particular patient population represents a severely psychotic sample: mean +/- SD PANSS total scores at baseline were 129.26 +/- 19.76. After I week of olanzapine treatment, mean PANSS total score was decreased significantly (-13.14; p < .001), as was mean PANSS total score after 6 weeks of olanzapine treatment (-45.16; p < .001); additionally, the positive subscale, negative subscale, and mood scores improved significantly. A significant improvement in the catatonic signs and symptoms composite score was also observed at week 6 (-4.96; p < .001). The mean +/- SD daily dose of olanzapine was 18.00 +/- 2.89 mg after 6 weeks of treatment. The present data analysis suggests the efficacy of olanzapine in the treatment of severely ill schizophrenic patients with nonspecified catatonic signs and symptoms.

Evidence for the effectiveness of olanzapine among patients nonresponsive and/or intolerant to risperidone.

BACKGROUND: This multicenter, open-label study evaluated the efficacy and safety of olanzapine in patients with schizophrenia who had been nonresponsive or intolerant to a course of risperidone (mean duration of risperidone treatment = 46.3 days). METHOD: A total of 34 patients with DSM-III-R and ICD-9 schizophrenia entered this trial. Twenty-five patients were nonresponsive to previous risperidone treatment, 6 patients were intolerant to the risperidone treatment, and 3 patients listed both reasons for discontinuation of risperidone. Patients were treated across a dose range of 5 to 25 mg/day of olanzapine. The primary efficacy variable was baseline to endpoint change in Positive and Negative Syndrome Scale (PANSS) score. Safety was assessed using the Clinical Global Impressions-Severity of Illness scale. RESULTS: Improvement from baseline PANSS score (mean +/- SD PANSS score = 119.4 +/- 26.9) was evident at the week-6 midpoint (-22.2 +/- 19.5) and at the week-14 endpoint (-28.7 +/- 22.3). On average, severity ratings were reduced from baseline by 25% after 14 weeks of olanzapine therapy. Twenty olanzapine-treated patients (58.8%) achieved the a priori-defined response criterion of > or = 20% reduction in PANSS total score. Among patients who met the response criterion, 50% (10/20) had done so by the fourth week. These clinical improvements occurred across a broad range of symptom domains and included reductions in PANSS positive, negative, general psychopathology, and mood subscores. No statistically significant differences were found on any efficacy measure at any visit between the patients who were nonresponsive to risperidone compared with those who were intolerant to risperidone. Olanzapine was well tolerated, with no subject discontinuing early owing to an intolerable adverse event that could be conclusively linked to olanzapine. CONCLUSION: The results of this open-label study suggest that olanzapine may be an effective alternative for schizophrenic patients who are nonresponsive and/or intolerant to risperidone treatment. Moreover, the results underscore the differential pharmacology that exists among the newer antipsychotic agents.

Efficacy of fluoxetine in Austrian patients with obsessive-compulsive disorder.

In an 8-week double-blind placebo-controlled trial we studied the efficacy of fluoxetine (FLX) in 53 Austrian patients with obsessive compulsive disorder (OCD) diagnosed according to DSM-III-R. The dosage of FLX was fixed at either 20, 40, or 60 mg per day. Response was prospectively defined as an at least 25% reduction on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and an improvement on Clinical Global Impression (CGI) rating to at least "much improved" at the endpoint. Patients treated with at least 40 mg FLX per day showed significantly higher response rates than did those receiving either placebo or FLX 20 mg/day. Compulsions were more reduced than obsessions and we also observed a strong placebo effect which is largely attributable to an improvement in the Y-BOCS compulsion subscore.

[Concomitant depression and its treatment]. / Die Begleitdepression und ihre Behandlung.

Accompanying depression is especially common in elderly, chronically ill patients and rehabilitation patients, where a physical illness and/or disablement is accompanied by depression. Treatment should always be focussed in a "polypragmatic" manner on both physical or psychic symptoms. In particular psychotherapy (see article by Barolin), pharmacotherapy (referred to in this article) and physiotherapy (described further in other literature) are of importance here. Advantage is to be taken of the polar dimensions of different types of antidepressant drugs, namely the increase in drive or sedating effects. However, the increased rate of side effects from some drugs among elderly patients is not to be ignored. Taking the above into consideration, the new antidepressant, Fluctine (Fluoxetine), has proved to be effective among our randomly selected patients. This is on account of its relatively fast onset of action, minimal side effects and its slight increase in drive. The group of non-responders (one third of the patients) showed no decrease in depressive symptoms when other antidepressants were substituted. As expected those patients suffering organic-brain illness responded worse and represent a large percentage of the non-responders. These data prove the results of previous findings that patients with organic-brain illness generally respond worse to antidepressant medication. Thus Fluctine can be recommended for elderly patients with accompanying depression.

[Efficacy and safety of fluoxetine versus clomipramine in ambulatory patients with a depressive syndrome in a clinical trial with private practitioners]. / Wirkung und Sicherheit von Fluoxetin versus Clomipramin bei ambulanten Patienten mit einem depressiven Syndrom in einer klinischen Prüfung bei niedergelassenen Arzten.

8 general practitioners and 7 specialists in the field of psychiatry and neurology participated in this study evaluating the results of fluoxetine treatment in outpatients with depression in respect to safety and efficacy. They were familiarized with the requisite instruments by video rater training. The study was designed as a randomised double-blind parallel study involving 139 patients, comparing the effects of a daily dosage of 20 mg fluoxetine, 40 mg fluoxetine and 50 mg clomipramine. The number of patients treated in each group was 45, 46, and 48, respectively and altogether 125 completed the four-week study (five visits). A comparison of overall efficacy ratings showed significant antidepressant efficacy in all three treatment groups. On day 14 of the study (visit 4), patients receiving 40 mg fluoxetine showed significantly (p less than 0.05) better global improvement than patients receiving clomipramine. Treatment was well tolerated by all patients. The frequency of adverse events in response to fluoxetine was lower than under clomipramine treatment. On comparing treatment by psychiatrist and general practitioner no significant differences were found regarding age, sex, number of previous episodes and duration of the recent episode and outcome. Severe depression tended to be treated by psychiatrists; general practitioners prescribed additional medication less frequently.