Efficacy and safety of the novel glycine transporter inhibitor BI 425809 once daily in patients with schizophrenia: a double-blind, randomised, placebo-controlled phase 2 study.

BACKGROUND: Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no approved pharmacotherapy is available. This study investigated whether the glycine transporter-1 inhibitor BI 425809 improves cognition in patients with schizophrenia. METHODS: This phase 2, randomised, double-blind, placebo-controlled, parallel-group trial (81 centres, 11 countries), randomly assigned outpatients (aged 18-50 years) with schizophrenia on stable treatment to add-on once-daily oral BI 425809 2 mg, 5 mg, 10 mg, or 25 mg or placebo (1:1:1:1:2) for 12 weeks. Treatment was assigned in blocks using interactive response technology; patients, investigators, and all trial personnel were masked to group assignment. The primary endpoint was change from baseline in MATRICS Consensus Cognitive Battery (MCCB) overall composite T-score at week 12. Six predefined dose-response models were evaluated using a multiple comparison procedure and modelling approach with mixed model repeated measures to assess evidence for a non-flat dose-response relationship for cognitive improvements with BI 425809. Adverse events were monitored. Safety analyses included all randomly allocated patients who received one or more doses of trial medication; efficacy analyses included patients from this set who also had available baseline data and at least one post-baseline on-treatment measurement for the primary or secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02832037. FINDINGS: 509 patients were randomly assigned between April 25, 2018, and Oct 4, 2019 (BI 425809 2 mg, n=85; 5 mg, n=84; 10 mg, n=85; 25 mg, n=85; placebo, n=170 444 (87%) completed the 12-week treatment. Five of six dose-response models showed a statistically significant benefit of BI 425809 over placebo (linear [t=2·55, p=0·015], linear in log [t=2·56, p=0·015]; Emax [t=2·75, p=0·0089], sigmoid Emax [t=2·98, p=0·0038], logistic [t=2·77, p=0·0085]). Pairwise comparisons showed greater mean improvement from baseline in MCCB overall composite T-score at week 12 with BI 425809 10 mg and 25 mg versus placebo (adjusted mean difference 1·98 [95% CI 0·43-3·53] for 10 mg and 1·73 [0·18-3·28] for 25 mg; standardised effect size 0·34 for 10 mg and 0·30 for 25 mg). Adverse events were balanced across groups, reported in 50 (59%) of 85 patients on BI 425809 2 mg, 44 (52%) of 84 on 5 mg, 35 (41%) of 85 on 10 mg, 36 (42%) of 85 on 25 mg, and 74 (44%) of 170 on placebo. INTERPRETATION: BI 425809 improved cognition after 12 weeks in patients with schizophrenia; doses of 10 mg and 25 mg showed the largest separation from placebo. If these encouraging results are confirmed in phase 3 trials, BI 425809 could provide an effective treatment for cognitive impairment associated with schizophrenia. FUNDING: Boehringer Ingelheim.

A comparison study of the turnaround time for telepsychiatry versus face-to-face consultations in general hospital nonpsychiatric emergency rooms.

BACKGROUND: Psychiatric consultation services, particularly for emergencies, are limited in many parts of the United States. Telepsychiatry services are helping to bridge the gap, and are gaining acceptance and popularity. There is paucity of publications regarding comparison of turnaround time for consultations between video conferencing and traditional face-to-face psychiatric consultations in general hospital nonpsychiatric emergency departments (EDs). Our study aimed to address turnaround time and patient satisfaction. METHODS: Data regarding the turnaround time for emergency psychiatric consultations using telepsychiatry in general hospital EDs was collected retrospectively and compared with the time for face-to-face traditional consultations. A patient satisfaction survey was also conducted after the telepsychiatry consultation. Statistical analysis of the data was done after the study was completed. RESULTS: The telepsychiatry group included 206 participants and the control group had 186 participants. There was an 84% reduction in the turnaround time for telepsychiatry consults (95% confidence interval, 81% to 86%). A patient satisfaction survey showed 97% satisfaction with telepsychiatry services. Gender and age did not modify the effect of telepsychiatry on time to consult (P > .10). CONCLUSIONS: The reduction in the turnaround time and improved patient satisfaction indicate that telepsychiatry services can improve the quality of care for patients in need of emergency services.

Evaluation of the Efficacy, Safety, and Tolerability of BI 409306, a Novel Phosphodiesterase 9 Inhibitor, in Cognitive Impairment in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled, Phase II Trial.

BACKGROUND: Patients with cognitive impairment associated with schizophrenia may benefit from treatments targeting dysfunctional glutamatergic neurotransmission. BI 409306, a potent and selective phosphodiesterase 9 inhibitor, was assessed in patients with schizophrenia using a learn-and-confirm adaptive trial design. METHODS: This double-blind, parallel-group trial randomized patients 2:1:1:1:1 to once-daily placebo or BI 409306 (10, 25, 50, or 100 mg) for 12 weeks. Stage 1 (learn) assessed change from baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) scores (week 12) to identify ≥1 meaningful endpoints for stage 2 (confirm). If no domains showed efficacy, change from baseline in Measurements and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) composite scores (week 12) was the primary endpoint. The key secondary endpoint was change from baseline in Schizophrenia Cognition Rating Scale (SCoRS) total score. Safety was monitored. RESULTS: Five hundred eighteen patients were randomized. In stage 1, CANTAB did not differentiate between BI 409306 and placebo (n = 120), so the primary endpoint of change from baseline in MCCB composite score was analyzed in 450 patients in stage 2. There was no significant difference between BI 409306 (1.2-2.8) and placebo (2.5) in MCCB composite score change. BI 409306 did not significantly improve change from baseline in SCoRS total score (-3.1 to -2.0) vs placebo (-2.5). Adverse events were dose-dependent, increasing from 33.3% (10 mg) to 53.5% (100 mg), vs 36.4% for placebo. CONCLUSION: The primary endpoint of cognitive function improvement was not met. BI 409306 was well-tolerated, with an acceptable safety profile.

Psychotropic drug changes contributing to readmissions in medically hospitalized psychiatric patients: A retrospective study.

BACKGROUND: Psychotropic drug changes during medical hospitalizations may lead to psychiatric and medical readmissions. METHODS: One-year hospitalization records of nursing home patients with chronic mental illness and a psychotropic drug change during medical admission were reviewed. We calculated the readmission rates for 30, 60, and 90 days; the classes of the psychotropic drugs changed; the reason for change; and the specialties of the responsible physicians. The readmission rates were compared with those of an age-matched control group. RESULTS: The changes were associated with an increase in psychiatric readmission rates of 2.7% (30 days), 5.4% (60 days), and 14.9% (90 days). The 90 days readmission rate reached statistical significance (14.9% vs 2.7%; OR = 6.29; P = .020). The family practice team was responsible for the highest psychiatric readmission rate (18.4%). The most significant reasons for change included human errors (up to 40%), which is alarming. CONCLUSIONS: Judicious changes, attempts at re-titration, and appropriate documentation of reasons for change on discharge records may reduce the readmission rates.

A Double-Blind, Placebo-Controlled Comparator Study of LY2140023 monohydrate in patients with schizophrenia.

BACKGROUND: Pomaglumetad methionil (LY2140023 monohydrate) is a potent and highly selective agonist for the metabotropic glutamate mGluR2 and mGluR3 receptors. We present results of a pivotal clinical study H8Y-MC-HBBM assessing the efficacy of LY2140023 in improving symptoms as a monotherapy in patients with an acute exacerbation of schizophrenia. METHODS: Enrolled adult patients (ages 18-65) with schizophrenia who had experienced an exacerbation of symptoms within 2 weeks prior to study entry. Patients (N = 1013) were randomized 2:2:2:1 to treatment with placebo, LY40 mg twice daily (BID), LY80 mg BID, or risperidone (RIS) 2 mg BID for 6 weeks after a one-week blinded placebo lead-in. The primary outcome assessed change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score in an overall schizophrenia population and a predefined subpopulation which excluded non-Hispanic white patients with the A/A genotype at the HTR2A SNP rs7330461. RESULTS: Neither LY2140023 dose showed significant improvement compared to placebo on PANSS total in either population (1-sided p-value [significance level], overall: LY40, p = .154 [0.01]; LY80, p = .698 [0.01], subpopulation: LY40, p = .033 [0.0025]; LY80, p = .659 [0.0025], MMRM analysis). RIS statistically separated from placebo in both populations (p < .001 [0.05]). There were no statistically significant differences in the incidence of serious adverse events, and no seizures on LY2140023. CONCLUSION: LY2140023 treatment did not demonstrate efficacy in populations studied. Overall, LY2140023 treatment was generally well tolerated with no new adverse safety findings compared to previous trials. Further understanding of the role of glutamate as a therapeutic target in schizophrenia is needed. CLINICAL TRIALS REGISTRATION: A Phase 2, Multicenter, Double-Blind, Placebo-Controlled Comparator Study of 2 Doses of LY2140023 Versus Placebo in Patients With DSM-IV-TR SchizophreniaClinicalTrials.gov identifier: NCT01086748.

Preadmission Screening and Resident Review (PASRR) regulation and its implications for patients, hospitals, nursing homes, and the taxpayers.

BACKGROUND: This study assessed the impact of the revision of the Preadmission Screening and Resident Review (PASRR) regulation changes in September 2011, which increased the turnaround time for PASRR evaluations from 3 to 5 days to 2 to 3 weeks. METHODS: From January 2013 to March 2013, we tracked all patients' charts in a 25-bed inpatient geriatric psychiatric unit in New York where PASRR evaluations were requested. The turnaround time and related issues were analyzed. RESULTS: There were 27 patients who had PASRR requests during the study period; 9 patients were not included in the study because of incomplete data. The average turnaround time for the 18 patients was 14.89 days and the additional hospital bed cost per patient was $11,911.11. CONCLUSIONS: Although PASRR has played a positive role in identifying persons with serious mental illness and the need to provide the services they need, the recent revision of the PASRR regulation in 2011 has significantly increased the hospital bed costs.

A current review of cytochrome P450 interactions of psychotropic drugs.

BACKGROUND: The number of psychotropic drugs has expanded tremendously over the past few decades with a proportional increase in drug-drug interactions. The majority of psychotropic agents are biotransformed by hepatic enzymes, which can lead to significant drug-drug interactions. Most drug-drug interactions of psychotropics occur at metabolic level involving the hepatic cytochrome P450 enzyme system. METHODS: We searched the National Library of Medicine, PsycINFO, and Cochrane reviews from 1981 to 2012 for original studies including clinical trials, double-blind, placebo-controlled studies, and randomized controlled trials. In addition, case reports, books, review articles, and hand-selected journals were utilized to supplement this review. RESULTS: Based on the clinical intensity of outcome, cytochrome interactions can be classified as severe, moderate, and mild. Severe interactions include effects that might be acutely life threatening. They are mainly inhibitory interactions with cardiovascular drugs. Moderate interactions include efficacy issues. Mild interactions include nonserious side effects, such as somnolence. CONCLUSIONS: Psychotropic drugs may interact with other prescribed medications used to treat concomitant medical illnesses. A thorough understanding of the most prescribed medications and patient education will help reduce the likelihood of potentially fatal drug-drug interactions.

Assessment of the effects of AZD3480 on cognitive function in patients with schizophrenia.

AZD3480 is a selective agonist of α4ß2 central neuronal nicotinic receptors (NNRs). This study investigated its effects on cognition, relative to placebo, in 440 patients with stable schizophrenia who were taking a single atypical antipsychotic medication and who were active cigarette smokers. Mean age was 41 (range 19 to 55) years and the majority of patients (88%) had a diagnosis of paranoid schizophrenia. Patients were randomized to one of 3 doses of AZD3480: 5 mg, 20 mg, and 35/100 mg (depending on CYP2D6 metabolic status), or to placebo. Treatment was given once daily for 12 weeks. The primary outcome measure was change in cognitive function from baseline to Week 12, as measured by IntegNeuro computerized test battery of cognitive function scores. Secondary outcome measures included assessment of functional capacity (University of California at San Diego Performance Based Skills Assessment [UPSA2]) and adaptive function (Social Functioning Scale [SFS]). AZD3480 failed to improve cognition relative to placebo in this population of patients or in subpopulations defined by disposition, metabolic status, antipsychotic treatment, age, age of illness onset, and sex. Likewise, no improvement relative to placebo was observed in either the SFS measure of adaptive functioning or the UPSA2 measure of functional capacity. AZD3480 was generally well tolerated in the population studied.

Primary prevention in psychiatry--adult populations.

BACKGROUND: The concept of prevention in psychiatry is unique. It includes promotion of mental health, identification of risk factors across the life cycle, and appropriate early interventions. Recent emphasis on intervention early in the development of mental illness has resulted in several preventive programs with varying degrees of success. METHODS: We reviewed the literature on primary prevention in mental health, categorizing reports as evidence of universal, selective, or indicated prevention. RESULTS: Indicated prevention through early intervention is the best-researched area of prevention in the spectrum of psychotic disorders, especially schizophrenia. Pharmacotherapy for ultra high-risk individuals combined with cognitive-behavioral therapy (CBT) has shown promising results in several studies. Strategies that teach younger individuals to cope with stress and provide psychosocial support have been effective in preventing mood and anxiety disorders. CONCLUSIONS: There is evidence that primary prevention may delay the onset of mental illness. Future research on the etiologies of mental illnesses is required to facilitate development of additional primary prevention strategies. These efforts may contribute to reallocation of resources and enactment of public policies that curb the staggering effects of mental illness on society.

Extrapyramidal symptoms associated with antidepressants--a review of the literature and an analysis of spontaneous reports.

BACKGROUND: Antidepressant-induced extrapyramidal symptoms (EPS) represent an underrecognized but important clinical entity. We reviewed the literature on new antidepressants and conducted an analysis of cases from the FDA Adverse Event Reporting System (AERS), which has not been published before. METHODS: A literature review was conducted using PubMed, Ovid, MEDLINE, PsycINFO, and the Cochrane Database. Search terms used were extrapyramidal, antidepressants, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine-dopamine reuptake inhibitors (NDRIs), miscellaneous antidepressants, and monoamine oxidase inhibitors (MAOIs). Inclusion criteria for the FDA AERS analysis were cases of EPS reported by physicians, cases where patients were on one antidepressant, and cases reported between July 2005 and March 2008. Reports of patients who were on concurrent psychotropics were excluded. RESULTS: Our literature review revealed 1 report each of EPS for duloxetine, nefazodone, and bupropion, 3 for escitalopram, and 4 for citalopram. For the FDA AERS analysis, 89 cases met our inclusion criteria: duloxetine was implicated in 66% of cases, sertraline in 10%, escitalopram in 7%, and bupropion in 6%. CONCLUSIONS: EPS have been reported with different classes of antidepressants, are not dose related, and can develop with short-term or long-term use. In view of the risk for significant morbidity and decreased quality of life, clinicians must be aware of the potential for any class of antidepressants to cause these adverse effects.

Cognitive status changes based on time of day in nursing home patients with and without dementia.

BACKGROUND: Changes in behavior and cognition have been observed with disruption of the circadian rhythm. METHODS: This study examined the effects of time of day (TOD) on administration of Mini-Mental State Examinations (MMSEs) in nursing home patients with dementia (patients) or functional psychiatric disorders (control), using repeated measures analyses of covariance (ANCOVAs). RESULTS: Controls (n = 34) scored significantly higher than patients (n = 38) on total MMSE and all subscales. Within the patients, men and women performed equally in the morning, but women performed marginally worse in the afternoon on total MMSE scores, orientation, and immediate recall and men performed significantly better in the afternoon. Within the control, no gender or time effects were detected. CONCLUSION: Results indicate that TOD had no significant impact on cognitive status in patients with dementia or patients with other psychiatric illnesses. No changes in activity timings are recommended in nursing home patients with dementia.

Pharmacological treatment of the psychosis of Alzheimer's disease: what is the best approach?

Psychosis of Alzheimer's disease (PAD) forms part of the behavioural and psychological symptoms of dementia (BPSD). PAD includes symptoms of psychosis such as hallucinations or delusions, and may be associated with agitation, negative symptoms or depression. Even though the US FDA has not approved any medication for the treatment of PAD, atypical antipsychotics have been widely used and favoured by geriatric experts in the management of the condition in view of their modest efficacy and relative safety. However, the recent FDA warnings regarding the cardiac, metabolic, cerebrovascular and mortality risks associated with the use of these drugs in elderly patients with dementia have caused serious concerns regarding their use. Nevertheless, until an effective and safe medication is approved by the regulatory agencies for PAD, clinicians do not have a better choice than atypical antipsychotics for the management of the serious symptoms of this condition.

The role of atypical antipsychotic agents in the treatment of schizophrenia and schizoaffective disorders in the elderly.

Schizophrenia and schizoaffective disorder are prevalent in 1% of the adult population. The condition was thought to predominantly affect the young however recent studies have shown that the condition occurs in individuals throughout the life-span. The aim of this review is to discuss the role of atypical antipsychotics in treating schizoaffective disorder and schizophrenia in the elderly. The advent of atypical antipsychotics has made significant strides in the pharmacotherapy of schizophrenia in the elderly. They are as efficacious as conventional agents in reducing the positive symptoms, possibly some what more efficacious in reducing negative symptoms and appear to have a relatively safer adverse effect profile. However metabolic side affects particularly glucose abnormalities and weight gain, cerebrovascular effects, and mortality risk noted in dementia patients are gaining increasing attention. Appropriate monitoring for the metabolic side effects has been recommended by agencies such as the FDA (United States Food and Drug Administration), ADA (American Diabetic Association) and APA (American Psychiatric Association). Treatment of elderly patients is complicated by age related biological factors affecting drug response and presence of comorbid medical conditions and concomitant medication. Current research supports the role of atypical antipsychotics in the treatment of schizophrenia and schizoaffective disorder in the elderly. Despite advantages compared with conventional agents, challenges to successful therapy remain, even with these better tolerated agents.

Psychological symptoms in paid caregivers of dementia patients: a pilot study.

OBJECTIVES: Determine symptoms, correlates, or predictors of depression and anxiety in paid caregivers of elderly persons with dementia. PARTICIPANTS: The 28 participants were paid caregivers of patients attending an adult day-care program for patients with Alzheimer disease. Each participant had a total score of 16+ or a score of 3+ on at least one item of the Problems and Complaints Inventory. MEASUREMENTS: PARTICIPANTS completed the Hamilton Depression (HAM-D) and Anxiety (HAM-A) scales and the Zarit Burden Interview. The total daily and weekly time that caregivers worked with their patients was recorded. RESULTS: Severity of depression (HAM-D scores) was significantly related to Zarit Burden Interview scores (p<0.001). In addition, HAM-D scores tended to be related to the number of hours per week provided by a caregiver (p=0.09). Severity of anxiety (HAM-A scores) tended to be related to Zarit Burden Interview scores (p=0.08). CONCLUSION: These findings indicate the need to devise strategies for alleviating work-related symptoms in paid caregivers.

Divalproex sodium in nursing home residents with possible or probable Alzheimer Disease complicated by agitation: a randomized, controlled trial.

OBJECTIVE: Three placebo-controlled clinical trials have suggested the benefit of valproate for treatment of agitation associated with dementia; one was used as the basis for this multicenter trial, conducted by the Alzheimer's Disease (AD) Cooperative Study. It addresses the efficacy, safety, and tolerability of divalproex sodium for the treatment of agitation associated with dementia. METHODS: This was a randomized, double-blind, placebo-controlled clinical trial in 153 nursing home residents with probable or possible AD complicated by agitation; 110 (72%) completed the trial. Participants were randomized to treatment with divalproex sodium at a target dose of 750 mg/day (N = 75) or placebo (N = 78) for 6 weeks. The primary outcome measure was change from baseline on the Brief Psychiatric Rating Scale (BPRS) Agitation factor. Secondary outcomes included total BPRS, Clinical Global Impression of Change, Cohen-Mansfield Agitation Inventory score, and measures of safety and tolerability. RESULTS: Compliance averaged 88%. Participants receiving divalproex achieved a mean dose of 800 mg/day. Change in mean BPRS Agitation factor scores did not differ between patients treated with divalproex and placebo, nor did secondary behavioral measures. Measures of safety and tolerability did not reveal clinically important drug/placebo differences. CONCLUSIONS: This multicenter trial showed no benefit of divalproex sodium for treatment for agitation in dementia at a mean dose of 800 mg/day over 6 weeks. The results do not support findings from previous trials indicating possible benefit.

Clinical experience with aripiprazole treatment in ten elderly patients with schizophrenia or schizoaffective disorder: retrospective case studies.

BACKGROUND: Clinical trials of aripiprazole, a recently Food and Drug Administration-approved atypical antipsychotic, included elderly patients, but more data are needed on the effects of aripiprazole in this population, especially those with comorbid medical illnesses. OBJECTIVE: To assess the response and safety of aripiprazole treatment in elderly patients with schizophrenia or schizoaffective disorder. METHOD: Data was obtained by retrospective review of medical records. Aripiprazole was used to treat 10 elderly hospitalized patients between 62 and 85 years of age who manifested signs of psychosis related to schizophrenia or schizoaffective disorder. All patients had been treated previously with atypical and classic antipsychotics. Response was assessed by clinical observation of patients' behavior and Clinical Global Impression Scale assigned retrospectively. RESULTS: Seven patients responded to treatment, two did not respond, and one had a partial response. The mean Clinical Global Impression Scale scores improved from 6 (severely ill) at baseline to 2.3 (much improved) at discharge. Treatment was discontinued in the two patients who did not respond. Of the seven patients who responded, four presented with positive symptoms and showed significant improvement while three presented with positive and negative symptoms and both symptoms improved significantly. Four patients had preexisting extrapyramidal symptoms (EPS) and these symptoms decreased in three patients. In addition, two patients were able to discontinue antiparkinson medications. One patient who had severe tardive dyskinesia showed significant improvement in the dyskinetic symptoms. Four patients showed postural hypotension (without clinical symptoms) which resolved over time without treatment. Six patients showed a mean weight loss of 5.2 lbs. No adverse consequences occurred when divalproex sodium, carbamazepine, clonazepam or citalopram were given concurrently. CONCLUSION: The reduction of both positive and negative symptoms of schizophrenia and the lack of significant EPS, tardive dyskinesia, sedation, weight gain, anticholinergic effects, and QTc prolongation gives preliminary indication that aripiprazole may be a safe and effective medication for elderly patients with schizophrenia or schizoaffective disorder.