Anticholinergic prophylaxis of acute haloperidol-induced acute dystonic reactions

Young adults treated with a high potency neuroleptic such as haloperidol are at high risk of developing dystonic reactions. In this retrospective study, 15 of 16 young adult patients treated only with haloperidol had such reactions within 60 hours of beginning the drug, while none of the seven patients treated with haloperidol plus prophylactic benztropine mesylate developed dystonia. Although methodologic considerations limit the generalization of these results, they are consistent with other reports and suggest that initial anticholinergic prophylaxis is warranted in young patients treated with high potency antipsychotics. All dystonic reactions in these patients occurred within 2 1/2 days, justifying the consideration of discontinuing prophylaxis (which also causes side effects) after 1 week.     

Plasma haloperidol and clinical response: a role for reduced haloperidol in antipsychotic activity?

Seventeen hospitalized psychotic patients were treated with a fixed oral dose of haloperidol, 5 mg twice daily for 28 days. Most were chronic schizophrenics with an acute exacerbation of their illness. All patients also received benztropine 3 mg twice daily during the last 11 days of the study, regardless of the presence or absence of extrapyramidal side effects. No significant linear or curvilinear relationship was found between steady state plasma levels of haloperidol and clinical response measured by total Brief Psychiatric Rating Scale score. At 28 days, the correlations between plasma levels and percent improvement were rs = 0.187 (not significant) for haloperidol and rs = 0.582 (p = 0.04) for the hydroxymetabolite, reduced haloperidol. The correlation for the sum was rs = 0.511 (p = 0.078). Metabolite levels were substantially higher than plasma haloperidol, on the average 2.7 times greater. Eleven days of benztropine treatment had no significant effect on haloperidol or metabolite plasma levels or on clinical status. At the end of the study, nine of 17 patients (53%) had recovered as judged by discharge readiness. Within the limitations implied by the small number of patients, these data suggest that reduced haloperidol is an important component of plasma antipsychotic activity and cannot be neglected in correlative studies, and that a substantial proportion of patients--about half--can be successfully treated with only 10 mg of haloperidol. The routine use of large doses is thus not necessary for many patients.     

Relationship between extrapyramidal symptoms and serum anticholinergic levels in treated chronic schizophrenics

Serum anticholinergic levels were measured by radioreceptor assay (RRA) in schizophrenic patients treated for drug-induced Parkinsonism; 68 patients stabilized on a single neuroleptic and an anticholinergic antiparkinsonian agent (benzhexol, benztropine or procyclidine) were assessed using the extrapyramidal side effects (EPS) scale prior to each blood sampling. Serum anticholinergic levels showed a significant inverse correlation with EPS but did not appear to be dose-related in any of the three anticholinergic drug groups. Percentage binding to proteins was significantly less with benztropine than either benzhexol or procyclidine. Serum-free anticholinergic levels correlated significantly with total serum levels in the benzhexol and procyclidine groups but not in the benztropine group. At serum levels above 4.5 pmol/ml atropine equivalents, EPS was significantly less than at levels below that. We discuss the implications of this finding and suggest practical clinical applications of measurement of serum anticholinergic levels. Serum neuroleptic and serum prolactin levels did not correlate with either dose or serum level of anticholinergics.     

Addition of lithium to haloperidol in non-affective,antipsychotic non-responsive schizophrenia: a double blind,placebo controlled,parallel design clinical trial

This double-blind placebo controlled, parallel design clinical trial compared the therapeutic effects of the addition of lithium or placebo to haloperidol in 21 seriously ill state hospital patients with DSM-III-R schizophrenia, who did not have concurrent affective disorders and who had not responded to previous trials of conventional antipsychotic medication. During a baseline period of 6 weeks, patients were switched to a stable dose of haloperidol (mean ± SD dose=13.6±8.1 mg/day). Patients were then randomized to receive either lithium or placebo in addition to haloperidol for 8 weeks (mean ± SD lithium level =0.98±0.13 mEq/1). Symptoms and side effects were assessed weekly. Improvement in symptoms correlated with the non-blind adjustment of antipsychotic dose, but not with lithium or placebo treatment. Side effects ratings did not differ between the two groups, but one patient developed a reversible delirium associated with combined lithium/haloperidol treatment. For these long-term, severely ill patients, combined treatment afforded no advantage over treatment with haloperidol alone.Supported by Grant MH 46700 from the National Institute for Mental Health. Lithium and lithium placebo capsules were supplied by Lilly Pharmaceuticals     

Epoetin Theta with a New Dosing Schedule in Anaemic Cancer Patients Receiving Nonplatinum-Based Chemotherapy: A Randomised Controlled Trial

INTRODUCTION: Recombinant human erythropoietin (r-HuEPO) is used to treat symptomatic anaemia due to chemotherapy. A new r-HuEPO, Epoetin theta (Eporatio?), was investigated and compared to placebo in a randomised, double-blind clinical trial in adult cancer patients receiving nonplatinum-based chemotherapy. The primary efficacy endpoint was the responder rate (complete haemoglobin (Hb) response, i.e., Hb increase ≥2 g/dl) without the benefit of a transfusion within the previous 4 weeks. RESEARCH DESIGN AND METHODS: 186 patients were randomised to s.c. treatment for 12 weeks with either Epoetin theta (N = 95) or placebo (N = 91). The starting dose was 20,000 IU once weekly Epoetin theta or placebo. RESULTS: The incidence of complete Hb responders was significantly higher in the Epoetin theta group than in the placebo group (72.6 vs. 25.3%, P < 0.0001). More patients in the placebo group than in the Epoetin theta group received blood transfusions after randomisation (23 patients, 25.3% vs. 13 patients, 13.7%, P = 0.0277). The majority of patients with a complete Hb response had 20,000 IU/week as their maximum dose prior to response, indicating that a dose of 20,000 IU is an appropriate starting dose. The overall frequencies of adverse events (AEs) were similar in both treatment groups. Hypertension was the only AE that was more frequent in the Epoetin theta group compared to the placebo group (8.4 vs. 1.1%). CONCLUSIONS: Epoetin theta showed a superior efficacy to placebo in terms of complete Hb response without blood transfusion within the previous 4 weeks. Treatment with Epoetin theta resulted in a statistically significant increase in mean haemoglobin levels compared to placebo. The overall frequencies of adverse events were similar in both treatment groups.     

An analysis of safety and tolerability data from controlled, comparative studies of quetiapine in patients with schizophrenia, focusing on extrapyramidal symptoms

AIM: This analysis evaluated the tolerability profile of quetiapine using data from all comparative controlled studies in patients with schizophrenia or related disorders in the AstraZeneca clinical trials database, focusing on extrapyramidal symptoms (EPS). METHODS: Adverse event (AE) data from randomised, double-blind, controlled studies in the AstraZeneca clinical trials database were pooled, allowing comparison of quetiapine (mean daily doses 357-496 mg/day) with placebo, haloperidol (10.4 mg/day), risperidone (5.5 mg/day) or chlorpromazine (552 mg/day). Incidence of EPS-related AEs in relation to quetiapine dose was also analysed using a subset of data from fixed-dose studies. RESULTS: Data from 4956 patients were analysed. Quetiapine was well tolerated, and did not increase EPS-related AEs when compared with placebo (9.6 vs. 10.6%, respectively). The incidence of EPS-related AEs with quetiapine was consistent across the dose range (4.2-13.2% vs. 11.1% with placebo). Patients receiving haloperidol, risperidone and chlorpromazine experienced significantly higher levels of EPS-related AEs than those on quetiapine. The most common quetiapine- associated AEs, with significantly higher incidence than placebo, were sedation, somnolence and orthostatic hypotension. CONCLUSION: Quetiapine is generally well tolerated in patients with schizophrenia or related disorders, with placebo-level EPS-related AEs. Quetiapine has a more favourable EPS profile than haloperidol, chlorpromazine or risperidone.     

Acute extrapyramidal side effects: Serum levels of neuroleptics and anticholinergics

An assay technique for measuring anticholinergic drugs in human serum based upon their inhibition of the specific binding of [³H]-quinuclidinyl benzilate to rat brain muscarinic receptors is described. The assay was validated by demonstrating a close correlation (r=0.99) between serum levels of nortriptyline measured by the radioenzymatic assay and a GLC technique. The assay measures free anticholinergics, and under standard assay conditions, approximately 95% of benztropine is bound to serum protein. Marked variation in serum anticholinergic levels in patients receiving the same oral dose was observed, and in individual patients there was a non-linear relationship between increasing oral dose and serum anticholinergic levels.In a cross-sectional study of 109 patients receiving concurrently neuroleptics and antichlinergics, there was no correlation (r=0.029) between serum neuroleptic levels measured by a radioreceptor assay and extrapyramidal side effects (EPS). In the patients whose serum anticholinergic levels were also determined, there was a significant inverse correlation (r=0.44) between anticholinergic levels and EPS. In this cohort of patients, there was no significant correlation between serum anticholinergic and serum neuroleptic levels (r=0.16) and the ratio of serum anticholinergic to serum neuroleptic was a poor predictor of EPS (r=0.26).The results suggest a marked variation in sensitivity of patients to the EPS-inducing of neuroleptics; nevertheless, the incidence of EPS decreases with increasing serum levels of anticholinergics. An optimal serum anticholinergic level of 10 pmole atropine equivalent per ml was associated with a low incidence of EPS and is relevant to drug action at the striatal muscarinic receptor.     

A randomised controlled study of risperidone and olanzapine for schizophrenic patients with neuroleptic-induced acute dystonia or parkinsonism

The objective of this study was to compare the effects of risperidone and olanzapine in schizophrenic patients with intolerant extrapyramidal side effects (EPS) on first generation antipsychotics. We conducted an 8-week, rater-blinded, flexible dose study. Seventy patients with schizophrenia, who met the DSM-IV research criteria of having neuroleptic-induced acute dystonia or parkinsonism, were randomly assigned to risperidone or olanzapine group. The primary outcome was a comparison of the incidence of concomitant anticholinergic drugs usage between the groups to manage their acute dystonia and parkinsonism. The average doses of risperidone and olanzapine from baseline to study end point were 1.8-3.5 mg/day and 7.7-11.7 mg/day, respectively. There were no significant differences in demographic data, severity of EPS or psychotic symptoms between the groups at baseline assessment. Patients taking risperidone had significantly higher incidence of using anticholinergic drugs to manage acute dystonia or parkinsonism overall during the study (OR = 5.17, 95%CI = 1.49-17.88, P = 0.013). There was no significant between-group difference in the changing of rating scales of EPS and psychotic symptoms. The results of our study favour olanzapine as a better choice in schizophrenic patients with intolerant EPS. Double-blinded, fixed dose and different ethnical study for EPS-intolerant schizophrenic patients is needed to confirm the results of our study.     

Extrapyramidal symptoms during treatment of first schizophrenia episode: Results from EUFEST

The European First Episode Schizophrenia Trial (EUFEST) included first-episode schizophrenia patients, assessing the efficacy of five antipsychotic drugs (haloperidol, amisulpride, olanzapine, quetiapine and ziprasidone) over one year. Baseline frequency of extrapyramidal symptoms (EPS) in this group of patients (n=490) was as follows: parkinsonism 10.8%, akathisia 10.0%, dystonia 1.8%, and dyskinesia 0.6%. The frequency of parkinsonism at baseline was greater in patients with a brief prior exposure to antipsychotics (≤2 weeks) compared with antipsychotic-naïve ones, and was positively correlated with the intensity of negative symptoms and negatively with depressive symptoms. After one month of treatment, the increase of parkinsonism was highest in patients receiving haloperidol (+13%), that of akathisia in patients treated with ziprasidone (+14%), and 10.1% of the patients were taking anticholinergic drugs, most frequently in the haloperidol group (24%). In 291 patients remaining on treatment after one year, both parkinsonism and akathisia had decreased: the frequency of parkinsonism was 3%, highest in the haloperidol group (9.1%), that of akathisia was 3%, highest in the quetiapine group (7.5%), and 4% of patients were taking anticholinergic drugs, most frequently those receiving haloperidol (10.5%). The results obtained suggest that in first-episode schizophrenia patients during the first year of antipsychotic treatment (in this case amisulpride, haloperidol in low doses, olanzapine, quetiapine and ziprasidone), EPS were present as manageable clinical problems.     

Flexible-dose clinical trials: predictors and outcomes of antipsychotic dose adjustments

In a new approach to the interpretation of data from flexible-dose studies, we examined the safety and efficacy measurements that preceded and followed dose changes, to identify clinical factors that predict dose change as well as subsequent outcome of clinical status with dose change. This was a post hoc analysis of 3 flexible-dosed olanzapine studies: acutely ill bipolar I patients with an index manic episode (N = 452) who received olanzapine (5-20 mg/d) or haloperidol (3-15 mg/d); acutely ill patients with schizophrenia (N = 339) who received olanzapine (10-20 mg/d) or risperidone (4-12 mg/d) for 28 weeks; and remitted bipolar I patients (N = 361) who received olanzapine (5-20 mg/d) or placebo for 48 weeks. The major findings of this analysis were: an increase in dose was predicted by baseline illness severity in the acute studies, and a decrease in dose was predicted by illness symptom improvement or worsening of adverse events. Dose decrease was followed by significantly decreased efficacy for patients with acute mania treated with olanzapine or haloperidol, and olanzapine dose increases were followed by improved efficacy. Treatment-emergent extrapyramidal symptom adverse events and akathisia typically predicted dose decreases. Techniques used in this analysis may prove to be useful in assessing the relationship between dose change and safety and efficacy measures.     

Olanzapine as alternative therapy for patients with haloperidol-induced extrapyramidal symptoms: results of a multicenter, collaborative trial in Latin America

Conventional antipsychotic agents can induce extrapyramidal symptoms (EPS) that may be alleviated by switching patients to novel agents such as olanzapine. Patients with schizophrenia and related disorders (ICD-10) who were taking haloperidol (N = 94; mean dose = 12.7 mg/day) and had EPS (Simpson-Angus Scale [SAS] > 3) were directly switched to 6 weeks of open-label olanzapine treatment (mean dose = 11.4 mg/day). There were significant mean improvements (p <0.001 for all measurements) from baseline to endpoint on the SAS (-9.69+/-5.33; percentage change, 87.2%), the Barnes Akathisia Scale (-1.00+/-1.19; percentage change, 82.5%), and the Abnormal Involuntary Movement Scale (-1.48+/-2.89; percentage change, 81.1%), and anticholinergic use decreased from 47.9% to 12.8% (mean baseline to endpoint change: -1.52+/-1.91-mg equivalents of benztropine; p < 0.001). Significant mean baseline to endpoint improvements (p < 0.001 for all measurements) were observed on the Positive and Negative Syndrome Scale (PANSS; -25.28+/-18.67; percentage change, 30.3%), the PANSS-extracted Brief Psychiatric Rating Scale (0-6 scale, -13.41+/-10.16; percentage change, 54.4%), and the Clinical Global Impressions Severity scale (-1.16+/-1.19; percentage change, 26.4%). Spontaneously reported treatment- emergent adverse events with a greater than 5% incidence were somnolence (16.0%), increased appetite (14.9%), weight gain (11.7%), headache (8.5%), anxiety (7.4%), dizziness (6.4%), and insomnia (5.3%). Criteria for a successful switch were met by 90.5% of patients. Psychotic symptom exacerbation was experienced by 30.9% of patients at any time during the study and by 11.7% of patients at endpoint. Results suggest that a direct switch to olanzapine is a therapeutic option when patients with haloperidol-induced EPS are unable to tolerate a more gradual switch.     

Clinical utility of nifedipine and diltiazem plasma levels in patients with angina pectoris receiving monotherapy and combination treatment

The clinical utility of nifedipine and diltiazem blood levels in patients with angina pectoris receiving monotherapy (N = 14) and combination treatment (N = 9) were assessed in a placebo run-in, double blind, randomized, crossover study. Compared to placebo, diltiazem (mean daily dose 360 mg), nifedipine (mean daily dose 90 mg) and combination diltiazem-nifedipine therapy (mean daily dose 55 mg of nifedipine, 360 mg of diltiazem) were associated with reductions in weekly angina attacks and nitroglycerin consumption. Although both drugs used as monotherapy and in combination were also associated with significant increments in exercise tolerance and other improved angina parameters, these changes were not related to the plasma levels of either drug. Nifedipine plasma levels were measured by gas chromatography and diltiazem plasma levels measured by reverse high-pressure liquid chromatography from specimens obtained 2-5 hours after the last previous dose, after 1, 2 and 3 weeks of treatment, and during baseline placebo and placebo washout periods. With combination therapy, there was no effect on the diltiazem plasma level compared to monotherapy. The significant decrease in the nifedipine dose in patients on combination therapy did not significantly change nifedipine plasma levels. Determinations of plasma levels of diltiazem and nifedipine in the management of patients is of no value in the management of patients with angina pectoris except for monitoring treatment compliance and overdosage.     

A randomized, double-blind, parallel-group comparison of venlafaxine and clomipramine in outpatients with major depression

A multicentre, randomized, double-blind study was conducted to compare the safety and antidepressant efficacy of venlafaxine and clomipramine in 102 outpatients with major depression. The patients received either venlafaxine or clomipramine at a dose titrated from 50 mg to a maximum of 150 mg/day during the first 2 weeks of treatment. Treatment was continued for up to 43 days. Montgomery Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAM-D) scores decreased significantly (p < or = 0.05) from baseline in each treatment group but were not significantly different between groups. Response rates on the MADRS and HAM-D were 62% and 59%, respectively, with venlafaxine and 54% and 43%, respectively, with clomipramine. Treatment-emergent study events were the primary reason for withdrawal in only 13% of venlafaxine-treated patients and 20% of clomipramine-treated patients. On questionnaires, the incidence of anticholinergic-type events was 60% with venlafaxine and 68% with clomipramine. However, significantly (p = 0.043) more patients in the clomipramine group reported multiple anticholinergic events than in the venlafaxine group. In the clomipramine group, mean ventricular heart rate increased significantly (p = 0.003) and mean systolic blood pressure decreased significantly (p = 0.028) from baseline, but no clinically significant electrocardiographic changes were observed. These results confirm the efficacy and safety of venlafaxine in the treatment of outpatients suffering from major depression.     

Gastrointestinal microbleeding associated with the use of etodolac, ibuprofen, indomethacin, and naproxen in normal males

Etodolac, a nonsteroidal antiinflammatory and analgesic drug, was used in a randomized, parallel group, open-label design study, with stool analysis conducted in a blind fashion, to compare its effect in normal men in doses of 400 mg (N = 11) and 600 mg (N = 12) b.i.d. on gastrointestinal microbleeding with that of 600 mg ibuprofen, q.i.d. (N = 12), 50 mg indomethacin in the morning, 50 mg at noon, and 100 mg h.s. (N = 9), and 375 mg naproxen b.i.d. (N = 9). Etodolac was given at about 2 1/2 and 3 1/2 times the mean effective dose used for treating patients with rheumatoid arthritis. The other drugs were given at their manufacturers' maximum recommended doses. Lead-in placebo was given for one week, active drug for one week, and washout placebo for one week. Fecal blood loss was measured by the 51Cr-tagged red cell method, and was averaged over days 4-7 (baseline), 11-14 (treatment period), and 17-20 (washout). The mean increase in blood loss for the treatment period for the 400 mg etodolac b.i.d. group (0.13 ml) and 600 mg etodolac b.i.d. group (0.10 ml) was significantly less (P = 0.001) than the corresponding values for ibuprofen (1.14 ml), indomethacin (1.20 ml), and naproxen (0.87 ml). There was no tendency for greater blood loss at higher doses of etodolac. Etodolac at doses in excess of the mean effective dose in osteoarthritis and rheumatoid arthritis caused significantly less microbleeding in normal male volunteers during the seven-day treatment period than the other drugs tested, and not clinically more than that occurring during baseline placebo.     

Clomipramine versus haloperidol in the treatment of autistic disorder: a double-blind, placebo-controlled, crossover study

Clomipramine, haloperidol, and placebo were compared with baseline in the treatment of autism, and overall outcome, specific symptoms, and side effects were examined. It was hypothesized that clomipramine would be better tolerated than haloperidol and prove superior on a measure of stereotypy. Individuals with a DSM-IV diagnosis of autistic disorder (mean age, 16.3 years; range, 10-36 years) were randomly assigned, by using a Latin square design, to the following 7-week trials: placebo, clomipramine (mean daily dose, 128.4 mg; range, 100-150 mg), or haloperidol (mean daily dose, 1.3 mg; range, 1-1.5 mg). Data on 36 subjects were analyzed and taken together; the results favored haloperidol. In those patients who were able to complete a full therapeutic trial, clomipramine proved comparable to haloperidol in terms of improvement compared with baseline. However, significantly fewer individuals receiving clomipramine versus haloperidol were able to complete the trial (37.5% vs. 69.7%, respectively) for reasons related to both side effects and efficacy or behavior problems. In the intent-to-treat sample, which is perhaps more clinically relevant, only haloperidol proved superior to baseline on a global measure of autistic symptom severity, as well as specific measures for irritability and hyperactivity. Clomipramine did not seem more effective on a measure of stereotypy, nor was it better tolerated.     

Differential reversal of various dopamine antagonists by anticholinergics in sidman avoidance: possible relationship to adrenergic blockade

Various dopamine receptor antagonists have divergent clinical and neurochemical properties. The relative ability of anticholinergics (benztropine and scopolamine) to reverse these drugs was assessed in squirrel monkeys and rats performing a Sidman avoidance task. In monkeys, benztropine markedly attenuated the effects of oxiperomide, metoclopramide, halopemide, tiapride and mezilamine as well as haloperidol. Chlorpromazine and fluphenazine were antagonized to a moderate extent; thioridazine and perlapine were not antagonized; and clozapine was actually potentiated by benztropine. In the rat, benztropine antagonized haloperidol strongly but reversed fluphenazine, thioridazine or clozapine only weakly or not at al. The overall effects of scopolamine in both species were similar to those of benztropine. The dopamine receptor antagonists that were most completely reversed by benztropine were found to inhibit ³H-spiroperidol more strongly than ³H-WB-4101 binding in calf caudate, while the reverse was true for drugs that were antagonized only moderately or not at all by benztropine. These results support a previous suggestion that anticholinergic reversal is less marked aginst dopamine antagonists with alpha-adrenergic blocking properties. Benztropine reversal of experimental dopamine receptor antagonists in the squirrel monkey Sidman avoidance test may contribute to their preclinical characterization.     

A double-blind comparison of sertraline and clomipramine in the treatment of major depressive disorder and associated anxiety in general practice

In this double-blind study in primary care patients, the efficacy and safety of sertraline, an antidepressant which is a selective inhibitor of serotonin re-uptake, was compared with clomipramine. Patients with DSM-III-defined major depression and with significant anxiety randomly received 50-150 mg of either sertraline (N=51) or clomipramine (N=55) once daily for 6 weeks. The mean final daily dose was 63.5 mg sertraline and 60.6 mg clomipramine. Seventy five percent of sertraline-treated and 79% of clomipramine-treated patients were maintained on the lowest dose of 50 mg once daily. The mean scores of all the rating scales (HAM-D, HAM-A, HAD, CGI) showed similar efficacy between the treatments in reducing the symptoms of depression and anxiety. Clomipramine was less well tolerated than sertraline with a greater overall incidence of side effects, or significantly greater incidence of anticholinergic side effects and significantly more patient withdrawals due to side effects; 18% in the clomipramine group compared with 4% in the sertraline group. The results indicate that sertraline is an effective agent to use in primary care patients with depression and associated symptoms of anxiety and is better tolerated than the tricyclic comparator clomipramine.     

Antipsychotic Augmentation of Serotonin Reuptake Inhibitors in Treatment-Resistant Obsessive-Compulsive Disorder: An Update Meta-Analysis of Double-Blind,Randomized, Placebo-Controlled Trials

Background:

Many patients with obsessive-compulsive disorder do not respond adequately to serotonin reuptake inhibitors. Augmentation with antipsychotic drugs can be beneficial in this regard. However, since new relevant randomized controlled trials evaluating new antipsychotics were conducted, a recalculation of the effect sizes appears necessary.

Methods:

We meta-analyzed all double-blind, randomized, placebo-controlled trials comparing augmentation of serotonin reuptake inhibitors with antipsychotics to placebo supplementation in treatment-resistant obsessive-compulsive disorder. The primary outcome was mean change in the Yale-Brown Obsessive–Compulsive Scale total score. Secondary outcomes were obsessions, compulsions, response rates, and attrition rates. The data collection process was conducted independently by 2 authors. Hedges’s g and risks ratios were calculated as effect sizes. In preplanned meta-regressions, subgroup analyses, and sensitivity analyses, we examined the robustness of the results and explored reasons for potential heterogeneity.

Results:

Altogether, 14 double-blind, randomized, placebo-controlled trials (n=491) investigating quetiapine (N=4, n=142), risperidone (N=4, n=132), aripiprazole (N=2, n=79), olanzapine (N=2, n=70), paliperidone (N=1, n=34), and haloperidol (N=1, n=34) were incorporated. Augmentation with antipsychotics was significantly more efficacious than placebo in Yale-Brown Obsessive–Compulsive Scale total reduction (N=14, n=478; Hedges’s g=-0.64, 95% CI: -0.87 to -0.41; P=<.01). Aripiprazole (Hedges’s g=-1.35), haloperidol (Hedges’s g=-0.82), and risperidone (Hedges’s g=-0.59) significantly outperformed placebo. Antipsychotics were superior to placebo in treating obsessions, compulsions, and achieving response. There was no between-group difference concerning all-cause discontinuation. The nonsignificant meta-regressions suggest no influence of the antipsychotic dose or baseline symptom severity on the meta-analytic results.

Conclusions:

According to our findings, antipsychotic augmentation of serotonin reuptake inhibitors can be regarded as an evidence-based measure in treatment-resistant obsessive-compulsive disorder.     

A review of the efficacy, tolerability and safety of sertindole in clinical trials

Sertindole is a non-sedating atypical antipsychotic agent with high selectivity for dopaminergic neurons in the mesolimbic system. In pivotal clinical trials, sertindole has demonstrated significantly greater efficacy than placebo against both the positive and negative symptoms of schizophrenia. In addition, sertindole has had at least similar efficacy to haloperidol and risperidone against positive symptoms, and significantly greater efficacy than haloperidol and risperidone against negative symptoms. The incidence of extrapyramidal symptom (EPS)-related adverse events and the rate of medication used to treat EPS in patients receiving clinically effective doses of sertindole in clinical trials were similar to those observed in placebo recipients and significantly less than those in haloperidol recipients. The incidence of QTc interval prolongation of 500 ms or greater with therapeutic dosages of sertindole has also been low. In general, sertindole has been well tolerated in clinical trials. Unlike other antipsychotic agents, sertindole has not been associated with cognitive impairment, and can actually improve cognitive function. Observational studies have shown that the efficacy and tolerability of sertindole observed in the clinical trial situation are emulated in a naturalistic setting. Large cohort analyses (N > 8000) have shown that all-cause and cardiovascular mortality is no greater with sertindole than with risperidone or olanzapine.     

Anticholinergic differences among patients receiving standard clinical doses of olanzapine or clozapine

This study evaluated anticholinergic effects among patients with schizophrenia, schizoaffective disorder, or bipolar I disorder who were receiving either olanzapine (N = 12) or clozapine (N = 12) at standard clinical doses in a naturalistic setting. Serum anticholinergic levels were determined in adult male and female subjects using a radioreceptor binding assay. The Udvalg for Kliniske Undersogelser Scale was used to evaluate anticholinergic side effects clinically, and the Mini-Mental State Examination provided a global cognitive measure. Patients had achieved target doses that were stable at the time at which blood samples were obtained, and no other concomitant medicine with known anticholinergic potential was allowed. Patients receiving olanzapine (average dose, 15 mg/day) had serum anticholinergic levels of 0.96 (+/-0.55) pmol/ atropine equivalents compared with levels of 5.47 (+/-3.33) pmol/atropine equivalents for those receiving clozapine (average dose, 444 mg/day) (p < 0.001). Rates of increased and decreased salivation were significantly more common among the clozapine- and olanzapine-treated patients, respectively, whereas constipation, urinary disturbances, and tachycardia/palpitations were significantly more common among clozapine-treated patients. Neither group showed any global cognitive deficits. Olanzapine-treated patients had serum anticholinergic levels that were less than one fifth those of the clozapine-treated patients. Furthermore, clinical evaluations confirmed that clozapine-treated patients experienced more frequent and severe anticholinergic side effects (except dry mouth). However, none of the patients in either group expressed any desire to discontinue these medications as a result of the anticholinergic side effects.