Educating physicians to reduce benzodiazepine use by elderly patients: a randomized controlled trial. Pharmacotherapy of impaired affect in recovering schizophrenic patients. Lithium combined with carbamazepine or haloperidol in the treatment of mania. Efficacy and tolerability of ziprasidone versus risperidone as augmentation in patients partially responsive to clozapine: a randomised controlled clinical trial. Efficacy of kava-kava in the treatment of non-psychotic anxiety, following pretreatment with benzodiazepines. Psychotherapy alone and combined with pharmacotherapy in the treatment of depression. The risks and benefits of clozapine versus chlorpromazine. A controlled trial of educational visiting to improve benzodiazepine prescribing in general practice. [Zotepine versus perazine in patients with paranoid schizophrenia: a double-blind controlled trial of its effectiveness].
Benzodiazepine use by elderly patients is associated with adverse outcomes including increased risk of falls and fractures, motor vehicle accidents and cognitive impairment. Recent studies suggest that individualized feedback and education to physicians may improve drug prescribing. In this study, we evaluated an intervention to address the inappropriate prescribing of benzodiazepines for elderly patients.
                We identified 1624 primary care physicians who wrote at least 10 prescriptions for the target drugs in a 2-month period and randomly assigned these physicians to the intervention group or the control group. We obtained data from the Ontario Drug Benefit claims database, which covers all Ontario residents aged 65 years and over for drugs selected from a minimally restrictive formulary. Every 2 months for 6 months, confidential profiles of benzodiazepine prescription use coupled with evidence-based educational bulletins were mailed to the intervention group. The control group received feedback and educational bulletins about first-line antihypertension drug prescribing for elderly patients. Our main outcome measures were reductions in the proportion of each physician's total benzodiazepine prescriptions for long-acting agents, combinations of benzodiazepines with other psychoactive medications (including other benzodiazepines) and long-term benzodiazepine therapy.
                After randomization, 168 physicians agreed to be in the intervention group and 206 in the control group. Their demographic and prescribing characteristics were similar. Although the proportion of long-acting benzodiazepine prescriptions decreased by 0.7% in the intervention group between the baseline period and the end of the intervention period (from 20.3%, or a mean of 29.5 prescriptions, to 19.6%, or a mean of 27.7 prescriptions) and increased by 1.1% in the control group (from 19.8%, or a mean of 26.4 prescriptions, to 20.9%, or a mean of 27.7 prescriptions) (p = 0.036), this difference was not clinically significant. There was no significant difference over the study period in either combination prescribing of benzodiazepines or in prescriptions for long-term benzodiazepine therapy.
                We did not find that a program of confidential feedback and educational material offered to Ontario primary care physicians had a clinically significant impact on their benzodiazepine prescribing. Prominent and persistent anxiety, depression, and/or negative features characterize a substantial minority of recovered or residually psychotic schizophrenic outpatients and contribute to poor outcome. Because extrapyramidal side effects of typical neuroleptic medications often resemble such features, we first systematically studied the contribution of extrapyramidal side effects to these problems and their treatment. For patients who remained distressed, controlled trials of supplemental thymoleptics were undertaken.
                In trial 1, 92 distressed (depressed and/or anxious) patients and 36 patients in a defect state (patients with negative symptoms) participated in a double-blind, intramuscular challenge that compared centrally acting benztropine mesylate with peripherally acting glycopyrrolate. In trial 2, 57 distressed patients and 22 patients in a defect state were randomly assigned to a double-blind, neuroleptic medication dose-reduction group. In trial 3, 57 chronically distressed patients who were maintained on a low dose of fluphenazine decanoate were randomly assigned to a supplemental desipramine hydrochloride, lithium carbonate, or placebo group under double-blind conditions for 12 weeks.
                For patients who were already maintained on antiparkinsonian medication, impaired affect was not resolved by additional benztropine. Only distressed patients with a family history of severe mental disorder (often affective) showed improvement with neuroleptic medication dose reduction. Patients in the defect-state group reported less dysphoria on a reduced neuroleptic medication dose, but negative symptoms persisted. Desipramine improved diverse aspects of mood and residual psychoticism, possibly as a prophylaxis against minor affective exacerbations. Depression improved in women only. Lithium positively affected multiple indexes of anxiety and anxious depression.
                Most often, persistent affective impairments are neither resistant extrapyramidal side effects nor characterological traits. Thymoleptics improve the nonphasic, chronic types of anxiety and depression in contrast to the acute, episodic forms, for which little support can be found in the literature. Hospitalized manic patients were withdrawn from psychoactive medications for 2 weeks after which they were randomized to double-blind treatment with carbamazepine plus lithium [CBZ-Li] or haloperidol plus lithium [HAL-Li] with benztropine. Unit dosages of Li 300 mg, CBZ 200 mg and HAL 2 mg were titrated to therapeutic plasma levels and maintained for 8 weeks. No rescue medications were permitted after 3 weeks. Standard ratings of psychopathology and side effects were accomplished weekly. Sixty patients entered the study but only 33 remained for randomization after drug washout. By 8 weeks both groups were improved from baseline without statistically reliable differences between them. However HAL-Li patients had more extrapyramidal side effects that were major reasons for dropout, whereas CBZ-Li patients were more often noncompliant and initially required more rescue medications. We conclude that either combination treatment can be beneficial but CBZ-Li has the advantage because of fewer neurologic side effects. Patients suffering from schizophrenic psychoses sometimes insufficiently respond to antipsychotic monotherapy and then combination approaches are preferred. We aimed in validating the add-on of ziprasidone and risperidone to clozapine, and we performed a randomised head-to-head trial. Patients with partial response to clozapine were randomly attributed to augmentation with ziprasidone (n = 12) or risperidone (n = 12). Efficacy assessments included the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS), the Hamilton Depression Scale (HAMD), the Clinical Global Impression (CGI) and the Global Assessment of Functioning (GAF). Furthermore, several safety and tolerability measures were obtained. After six weeks, both groups showed significant reductions of positive and negative symptoms. In addition, affective state, psychosocial functioning and clozapine side effects improved without significant differences between the groups. Both approaches were well tolerated. However, the ziprasidone group experienced a small elongation of the QTc interval and a reduction of extrapyramidal symptoms. Patients under clozapine-risperidone therapy developed a rise of serum prolactin levels. The clozapine augmentation with ziprasidone or risperidone resulted in significant psychopathological improvements. The side effects differed between the treatment groups. Further head-to-head comparisons of atypical antipsychotics as add-on to clozapine are necessary. A 5-week randomized, placebo-controlled, double-blind study was carried out to investigate the efficacy of kava-kava special extract WS1490 in non-psychotic nervous anxiety, tension and restlessness states. During the first treatment week, the study dose drug was increased from 50 mg to 300 mg per day and pretreatment with benzodiazepines was tapered off over 2 weeks. These dosage adjustments were followed by 3 weeks of monotherapy with WS1490 or placebo. Outcome measures were the differences between baseline and end of treatment on the Hamilton Anxiety Scale (HAMA) and on a subjective well-being scale (Bf-S), as well as the benzodiazepine withdrawal symptoms. Changes in the Erlanger Anxiety, Tension and Aggression Scale (EAAS) and Clinical Global Impressions (CGI) were analyzed as secondary measures. Treatment safety was checked by interviews, adverse event reports and laboratory investigations. Forty patients (2x20) were included into the study. WS1490 was superior to placebo regarding the HAMA (P=0.01) and Bf-S (P=0.002) total scores and all secondary efficacy measures. The tolerance of WS1490 was not inferior to placebo. The study confirms the anxiolytic efficacy and good tolerance of WS1490 and shows that a further symptom reduction is possible after a change-over from benzodiazepine treatment. The relative efficacy of psychotherapy and combined therapy in the treatment of depression is still a matter of debate.
                To investigate whether combined therapy has advantages over psychotherapy alone.
                A 6-month randomised clinical trial compared Short Psychodynamic Supportive Psychotherapy (n=106) with combined therapy (n=85) in ambulatory patients with mild or moderate major depressive disorder diagnosed using DSM-IV criteria. Antidepressants were prescribed according to a protocol providing four successive steps in case of intolerance or inefficacy: venlafaxine, selective serotonin reuptake inhibitor, nortriptyline and nortriptyline plus lithium. Efficacy was assessed using the 17-item Hamilton Rating Scale for Depression, the Clinical Global Impression of Severity and of Improvement, and the depression sub-scale of the Symptom Checklist.
                The advantages of combining antidepressants with psychotherapy were equivocal. Neither the treating clinicians nor the independent observers were able to ascertain them, but the patients experienced them clearly.
                The advantages of combining antidepressants with psychotherapy are equivocal. Clozapine is an atypical antipsychotic drug with reduced risk of unwanted neurological effects in comparison with other drugs. In this multicenter study, 151 hospitalized schizophrenic patients were randomly assigned to treatment under double-blind conditions to assess the antipsychotic efficacy and safety of clozapine versus chlorpromazine. All patients exhibited tardive dyskinesia or other extrapyramidal side effects associated with at least two prior neuroleptics. Eleven patients were dropped from treatment due to extrapyramidal symptoms while being treated with chlorpromazine; only one clozapine patient's treatment was terminated for this reason. Clozapine patients exhibited clinical improvement superior to that of chlorpromazine patients as assessed by the Brief Psychiatric Rating and Clinical Global Impression scales. These results suggest that clozapine is well tolerated and may be therapeutically superior to chlorpromazine in treating psychotic behavior. Agranulocytosis potential can be minimized by frequent white blood cell counts and removing nonresponding patients from treatment prior to the peak risk period (months 2 through 6). A randomised controlled trial studied the effect of an educational visit on benzodiazepine prescribing. An approximately representative sample of 286 general practitioners was allocated to an intervention or a control group. Rates of benzodiazepine prescriptions were derived from two comprehensive self-report surveys seven months apart. Two months after the first survey the intervention group received an educational visit and supporting material from a doctor or pharmacist, ostensibly unconnected with the surveys. The overall benzodiazepine prescribing rate fell by 23.7 per cent from the first to the second surveys, from 4.93 to 3.76 prescriptions per 100 encounters (P < 0.001). Anxiety and insomnia diagnosis rates also declined from 4.68 to 3.76 per 100 encounters (19.7 per cent). After adjusting for confounders, there was a differential downward trend in prescriptions per diagnosis of insomnia but not to a statistical level. The same was true of initial prescriptions per insomnia diagnosis. In a subsidiary analysis selecting only new insomnia diagnoses, the intervention had a strong effect in reducing initial prescriptions (odds ratio 0.18, 95 per cent confidence interval 0.04 to 0.73). No effect was seen on prescribing for anxiety diagnoses. Educational practice visiting for benzodiazepine prescribing in anxiety, as we conducted it, is not justified in an unselected population of general practitioners. Specific education on prescribing for insomnia is probably useful. Our interpretation of the reduction in benzodiazepine prescribing is that probably there was an effect from self-monitoring alone which overwhelmed a main-analysis intervention effect. Retrospective diagnosis may also have obscured a real intervention effect. The dibenzothiepine zotepine is a new potential "atypical" neuroleptic exhibiting powerful antiserotonergic and antidopaminergic properties. The efficacy of zotepine was evaluated in a double-blind controlled trial versus the tricyclic neuroleptic perazine in 41 patients suffering mainly from the paranoid-hallucinatory type of schizophrenia. The key outcome variable was the extent of mental disturbance as defined by the total score of the BPRS. Additional outcome variables were GAS and CGI. In addition, adverse reactions and extrapyramidal side effects were assessed according to the FSUCL scale and the Gerlach and AIMS rating scale, respectively. Additional variables recorded were blood pressure, heart rate and routine laboratory parameters as well as electrocardiogram and electroencephalogram. In the first two days, standard equivalent doses of both drugs were administered. Thereafter, doses were administered as required. The efficacy of both substances was compared after 7, 14 and 28 days of treatment. Both drugs showed a similar antipsychotic efficacy. Under zotepine treatment a 55% improvement of the BPRS total score was observed while perazine led to a 41% BPRS score reduction. After 7 days the zotepine group was significantly more improved than the perazine group, possibly due to a dosing effect in the perazine group. In the zotepine group, fewer adverse reactions and a better benefit/risk index were observed although the differences between the two treatment groups did not reach levels of statistical significance. There were no drug-specific abnormal laboratory findings. Thus, in the present study there was no significant difference between zotepine and perazine with respect to antipsychotic efficacy and side-effect rates. However, zotepine showed a trend to a better benefit/risk index at the end of treatment.
The potential benefits of adding a benzodiazepine to an antidepressant must be balanced judiciously against possible harms including development of dependence and accident proneness, on the one hand, and against continued suffering following no response and drop out, on the other.