Expert consensus recommendations on the use of randomized clinical trials for drug approval in psychiatry- comparing trial designs.

The use of randomized clinical trials, in particular placebo-controlled trials, for drug approval, is the subject of long-standing debate in the scientific community and beyond. This study offers consensus recommendations from clinical and academic experts to guide the selection of clinical trial design in psychiatry. Forty-one highly cited clinical psychiatrists and/or researchers participated in a Delphi survey. Consensus statements were developed based on the findings of a published, peer-reviewed systematic review. Participants evaluated statements in two survey rounds, following the Delphi method. The expert panel achieved consensus on 7 of 21 recommendations regarding the use of randomized clinical trials. The endorsed recommendations were: (i) Results from placebo-controlled trials are the most reliable and (ii) are necessary despite the growing placebo-effect; (iii) it is ethical to enroll patients in placebo-arms when established treatment is available, if there is no evidence of increased health risk; (iv) There is a need to approve new drugs with the same efficacy as existing treatments, but with different side-effect profiles; (v) Non-inferiority trials incur an increased risk of approving ineffective medications; (vi) The risk of approving an ineffective drug justifies trial designs that incur higher costs, and (vii) superiority trials incur the risk of rejecting potentially efficacious treatments. The endorsed recommendations inform the choice of trial-design appropriate for approval of psychopharmacological drugs. The recommendations strongly support the use of randomized clinical trials in general, and the use of placebo-controlled trials in particular.

Tetrabenazine for tardive tremor in elderly adults: a prospective follow-up study.

Tardive tremor (TT) is a rare neuroleptic-induced tardive syndrome. It is mainly postural and action associated rather than resting tremor without other parkinsonian features and resistant to most therapeutic interventions. Tetrabenazine (TBZ) is a possible option for treating TT.This study aimed to evaluate the efficacy and tolerability of TBZ in elderly patients with TT. Patients (N = 10) received TBZ (25-150 mg/d) for 6 weeks. Five subjects completed the study. Mean TBZ dose at study end was 57.5 ± 37.3 mg/d. Mean Abnormal Involuntary Movement score was 13.3 ± 6.6, mean Tremor Scale score was 2.3 ± 0.9, mean Clinical Global Impression-Change was 3.6 ± 2.2, and mean Geriatric Depression Score was 5.2 ± 4.9; all not significantly changed from baseline. Five patients suffered side effects, including depression (n = 3), parkinsonism (n = 2), akathisia (n = 1), and mild stroke (n = 1).This prospective study does not support TBZ treatment for TT in elderly psychiatric patients.

Effectiveness and safety of clozapine in elderly patients with chronic resistant schizophrenia.

UNLABELLED: ABSTRACT Background: Recommendations for the treatment of elderly schizophrenia patients are largely based on data extrapolated from studies of antipsychotic medications in younger patient populations. We aimed to evaluate the effectiveness and safety of clozapine monotherapy in a diagnostically homogeneous group of elderly patients suffering from schizophrenia (DSM-IV-TR criteria). METHODS: A retrospective analysis of computerized medical charts of elderly inpatients suffering from schizophrenia treated at our center during the period January 2007-December 2012 was undertaken. Inclusion criteria were: (1) 60 years and older, (2) unsuccessful treatment with at least three different antipsychotic compounds during the last five years prior to the study period. Mortality and re-hospitalization over a five-year period were the pre-defined outcome measures. RESULTS: Of 527 elderly patients suffering from schizophrenia 43 patients, mean age 69.4 ± 8.7 years, were treated with clozapine. There were 19 women and 24 men, mean disease duration was 38.8 years. All had been exposed to at least three first- and second-generation antipsychotics prior to clozapine treatment. Clozapine was very well tolerated by the patients and mortality rate (8/43 (18.6% vs. 87/484 (18%)) was equal to that of other first- and second-generation antipsychotics (p < 0.18). Re-hospitalization rates with clozapine were significantly lower than rates for the five-year period prior to exposure to clozapine (0.41 vs. 3.8; p < 0.001). CONCLUSION: The present study demonstrates that clozapine is efficacious and safe for the treatment of elderly schizophrenia patients. Prospective studies are needed to support these findings.

Amisulpride for older patients with long-standing schizophrenia.

A large and growing number of older people across the world experience schizophrenia. Recommendations for their treatment are largely based on data extrapolated from studies of the use of antipsychotic medications in younger populations. The present study was designed to evaluate the efficacy and safety of amisulpride monotherapy in a diagnostically homogeneous group of elderly patients without cognitive impairment experiencing schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for schizophrenia). Mortality and rehospitalization for a 5-year period were the predefined outcome measures. We conducted a retrospective chart review of all elderly (60 years and older) schizophrenia patients treated in a large tertiary care center. Of the 527 elderly schizophrenia patients for a 5-year period (2007-2013), 30 patients, mean (SD) age of 67.5 (5.8) years, were treated with amisulpride monotherapy. There were 19 women and 11 men in the analyzed group. Mean duration of disease was 34.4 years. All had been exposed to at least 3 first- and second-generation antipsychotics before amisulpride treatment. Amisulpride was very well tolerated by the patients, and mortality rate (10% vs 19%) was significantly lower than that of other first- and second-generation antipsychotics (P < 0.02). Rehospitalization rates with amisulpride were significantly lower than those with other second-generation antipsychotics (P < 0.001). We tentatively conclude that our preliminary results demonstrate that amisulpride is an efficacious and safe atypical antipsychotic for the treatment for elderly schizophrenia patients.

Venlafaxine or a second SSRI: Switching after treatment failure with an SSRI among depressed inpatients: a retrospective analysis.

BACKGROUND: Approximately 50% of patients with major depressive disorder (MDD) do not respond after adequate first-line treatment with a selective serotonin reuptake inhibitor (SSRI). Special interest is paid to whether specialist level inpatient psychiatric care results differ from community studies. AIM: To compare switching alternatives after treatment failure with an SSRI; switching to venlafaxine (Dexcel Pharma Israel) versus switching to another SSRI in depressed inpatients. METHOD: A retrospective register study of inpatients was undertaken in a psychiatric tertiary care university center serving an urban catchment area in Israel with a population of more than 900,000. RESULTS: A total of 401 MDD inpatients were assigned to antidepressant treatment. Of these, 232 records (47 venlafaxine, 185 SSRI) were included in the analysis. Patients assigned to venlafaxine treatment were older (mean age 64.3 ± 15 years versus 53.6 ± 17; p<0.01) and had more comorbid physical disorders (80% versus 57%; p<0.001). In the primary analysis, there was no statistical difference between groups in reduction in CGI-S total scores. The secondary end point of achieving a CGI-S score of 2 or less (1 = normal, not at all ill or 2 = borderline mentally ill) was statistically significantly better for the venlafaxine treated inpatients (P=0.02). AEs were reported less than 10% of patients in both groups. CONCLUSION: Patients who remain severely depressed following treatment with an SSRI may gain benefit from the dual-action drug venlafaxine, rather than switching to another SSRI. These findings need to be further supported by prospective studies.

Assessing cardiovascular risks of olanzapine treatment: a 6-month study versus haloperidol in schizophrenia patients.

The introduction of second generation antipsychotics (SGA) represents a major advance in the treatment of schizophrenia. Concerns about the metabolic and cardiovascular adverse effects of the SGA have been widely disseminated. The benefits and risks of these drugs have been studied with a focus on particular organ systems. A basic principle of prevention is that the intensity of risk-reduction therapy should be adjusted to a individual's absolute risk. Hence, the first step is to assess an individual's risk status. The present study was designed to evaluate whether there is an added cardiovascular disease (CVD) risk in switching schizophrenia patients from typical antipsychotics to the SGA olanzapine. Risk status was determined by a 10-year risk assessment as recommended by the USA National Heart, Lung, and Blood Institute. This was carried out with Framingham scoring to identify individuals whose short-term (10-year) risk warrants consideration of intensive treatment. This risk was calculated for schizophrenia patients who were treated by haloperidol for a minimum period of 6 months and again following 6 months of exposure to olanzapine. Forty-three patients fulfilled inclusion criteria. There were 25 male and 18 female patients (mean age 40.7+/-2.4 years). The mean 10-year percentage risk of CVD for the group while on haloperidol treatment was 4.58+/-0.9 and, after 6 months of exposure to olanzapine, this was reduced to 4.12+/-0.9. Changes in the total risk and each evaluated risk variable were not statistically significant, except for a decrease in resting systolic blood pressure. Switching schizophrenia patients from typical antipsychotic treatment to olanzapine is safe and does not increase the long-term risk of cardiovascular disease.

Increased risk of attempted suicide among aging holocaust survivors.

OBJECTIVE: Suicide rates are higher in elderly persons than in those at other phase of the life-cycle. The majority of World War II (WWII) veterans and Holocaust survivors still define their war experiences as being the "most significant stressor" of their lives. Aging of survivors is frequently associated with depression, reactivation of traumatic syndromes, physical disorders, loss, and psychological distress, possibly increasing the risk of suicide. The aim of the present study was to investigate, among a large cohort of elderly Holocaust survivors, whether their WWII experiences confer an increased risk of suicidal behavior. METHODS: All medical records of elderly patients admitted to a psychiatric hospital in Israel during a 5-year period were retrospectively evaluated. Suicidal patients were compared with patients who had not attempted suicide. RESULTS: Of 921 eligible patients, 374 were Holocaust survivors; 135 (14.6%) had attempted suicide in the month before admission. Ninety Holocaust survivors (24%) had attempted suicide, versus 45 of the 502 patients (8.2%) with no WWII experience. The risk of attempted suicide among Holocaust survivors was significantly increased. CONCLUSION: Although these findings are from a highly selected sample, we suggest that aging Holocaust survivors are at increased risk of attempting suicide. The growth of the elderly population, of whom many had had traumatic life experiences, emphasizes the need to implement preventive strategies so that suicidal risk may be contained.

Patients' satisfaction with psychiatric inpatient care.

BACKGROUND: Patient satisfaction with medical treatment is important, and although in mental health the literature on the topic is scant, awareness of the issue is rapidly growing. AIM: Evaluation of patient satisfaction among hospitalized psychiatric patients. METHODS: 100 consenting patients (47 men and 53 women) were surveyed and completed a questionnaire regarding satisfaction with psychiatric care. SETTING: Fifty-nine percent of the patients were in a new modern building, 41% were in an older hospital building; 21% were in a psycho-geriatric ward. The various settings allowed comparison across different environments. RESULTS: Most participants expressed mild general satisfaction. The overall rating was 3.40 +/- 0.43 (range 1-5). The ratings were similar regarding the various components of treatment: satisfaction with the nursing staff, physical conditions on the ward and treatment per se. Positive correlation was found between satisfaction with nursing and overall ratings. CONCLUSION: Inpatients were mildly satisfied with treatment. However, no correlation was found between satisfaction and either the type of case manager or the physical conditions in the ward. Further research is needed to characterize specific variables that may influence patient satisfaction with psychiatric care. In addition, the question of whether self-report evaluation questionnaires are appropriate for the inpatient psychiatric population should be addressed.

Aggression: the testosterone-serotonin link.

The relevance of central neurotransmission to aggressive and impulsive behavior has become more evident due to extensive research in humans and animals. Among other findings, there are abundant data relating low serotonergic activity--as measured by low cerebrospinal fluid 5-hydroxyindolacetic acid, and a blunted response of prolactin to fenfluramine--to impulsive behavior. Many studies on testosterone activity show a relation between high plasma levels and a tendency towards aggression. It is hypothesized that the interaction between low serotonin and high testosterone levels in the central nervous system has a significant effect on the neural mechanisms involved in the expression of aggressive behavior. It seems that testosterone modulates serotonergic receptor activity in a way that directly affects aggression, fear and anxiety. Our survey reviews the main findings on serotonin, testosterone and the possible interaction between them with regard to these behavioral phenomena.

Age-related differences in the side effect profile of citalopram.

The authors evaluated the autonomic and cardiovascular side effects of citalopram with particular emphasis on their relation to the age of treated patients. The data that formed the basis for the U.S. Food and Drug Administration approval of citalopram were provided by Lundbeck (Copenhagen, Denmark). This database included placebo-controlled short- and long-term studies in major depressed patients. The list of side effects comprised all "heart rate and rhythm disorders" as well as "autonomic nervous system disorders" that had been reported by at least 5% more than that reported for the placebo group of subjects. The database encompassed 1344 subjects treated with citalopram (20-60 mg/day) for a period of no less than 6 weeks. Statistically significant age-related distribution was found for five side effects: bradycardia, nausea, diarrhea, sweating and headache. Bradycardia was more prevalent in elderly (>65 years) patients as compared to the younger population (2.4% vs. 0.2%, P<.05), whereas gastrointestinal side effects, sweating and headache were less prevalent in the elderly. The age-related differences in the side effect profile may be attributable to altered sensitivity of the serotonergic system.

Suicide in Israel: 1985-1997.

OBJECTIVE: To examine trends in suicide rates in Israel over a 13-year period. METHOD: All cases of autopsy-confirmed suicide in Israel from 1985 to 1997 were retrospectively reviewed. RESULTS: An overall annual increase in suicide rates, with rates in men 3 times higher than those in women, was observed. Suicide rates were highest in the second and third decades of life. Unlike Western countries where gunshot wounds are the most common method of suicide for men and poisoning is most common for women, asphyxiation by hanging was the most common method used by men in Israel, followed by firearm wounds and jumping from heights. In women, however, jumping from heights was the most common method, followed by hanging and poisoning. CONCLUSION: Increasing rates of suicide may be associated with waves of immigration to Israel, increased substance abuse and depression and the political and social climate. Further study to examine the precipitating factors is warranted.