Optimizing long-term response to methadone maintenance treatment: a 152-week follow-up using higher-dose methadone

We report the clinical course over 152 weeks of 245 patients in methadone maintenance treatment: 144 high dose (HD) patients (> or = 100 mg/d, mean 211 mg/d), and 101 control (C) patients (< 100 mg/d, mean 65 mg/d). After 152 weeks the mean methadone doses were 284.9 mg/d (range 13-1100 mg/d) and 94.0 mg/d (range 10-500 mg/d), respectively. Overall retention in treatment was 59% over the 152 weeks, with the HD group having significantly better retention (61.1% vs. 46.3%) and lower rates of positive urine toxicologies (16.0% vs. 36.6%). Mortality was statistically the same for the HD group (2/144, 1.4%) and the C group (2/101, 1.9%) over the 152-week period. We conclude that doses of methadone exceeding 100 mg/d are safe and effective in long-term maintenance treatment. We attribute the favorable outcomes we report to a model of treatment that emphasizes medication management in the treatment of opioid addiction.     

Paroxetine: an update of its use in psychiatric disorders in adults

Paroxetine is a selective serotonin reuptake inhibitor (SSRI), with antidepressant and anxiolytic activity. In 6- to 24-week well designed trials, oral paroxetine 10 to 50 mg/day was significantly more effective than placebo, at least as effective as tricyclic antidepressants (TCAs) and as effective as other SSRIs and other antidepressants in the treatment of major depressive disorder. Relapse or recurrence over 1 year after the initial response was significantly lower with paroxetine 10 to 50 mg/day than with placebo and similar to that with imipramine 50 to 275 mg/day. The efficacy of paroxetine 10 to 40 mg/day was similar to that of TCAs and fluoxetine 20 to 60 mg/day in 6- to 12-week trials in patients aged > or =60 years with major depression. Paroxetine 10 to 40 mg/day improved depressive symptoms to an extent similar to that of TCAs in patients with comorbid illness, and was more effective than placebo in the treatment of dysthymia and minor depression. Paroxetine 20 to 60 mg/day was more effective than placebo after 8 to 12 weeks' treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder (social phobia), generalised anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Improvement was maintained or relapse was prevented for 24 weeks to 1 year in patients with OCD, panic disorder, social anxiety disorder or GAD. The efficacy of paroxetine was similar to that of other SSRIs in patients with OCD and panic disorder and similar to that of imipramine but greater than that of 2'chlordesmethyldiazepam in patients with GAD. Paroxetine is generally well tolerated in adults, elderly individuals and patients with comorbid illness, with a tolerability profile similar to that of other SSRIs. The most common adverse events with paroxetine were nausea, sexual dysfunction, somnolence, asthenia, headache, constipation, dizziness, sweating, tremor and decreased appetite. In conclusion, paroxetine, in common with other SSRIs, is generally better tolerated than TCAs and is a first-line treatment option for major depressive disorder, dysthymia or minor depression. Like other SSRIs, paroxetine is also an appropriate first-line therapy for OCD, panic disorder, social anxiety disorder, GAD and PTSD. Notably, paroxetine is the only SSRI currently approved for the treatment of social anxiety disorder and GAD, which makes it the only drug of its class indicated for all five anxiety disorders in addition to major depressive disorder. Thus, given the high degree of psychiatric comorbidity of depression and anxiety, paroxetine is an important first-line option for the treatment of major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD and PTSD.     

Setting New Standards for the Pharmacological Treatment of Panic Disorder

Three drugs are currently licensed for the treatment of panic disorder: the benzodiazepine, alprazolam; the tricyclic antidepressant, clomipramine; and, most recently, the selective serotonin reuptake inhibitor, paroxetine. Alprazolam and clomipramine are effective in the treatment of panic disorder, but are less than ideal agents due to their tolerability profiles. An extensive clinical trial programme has been undertaken to investigate the efficacy and tolerability of paroxetine treatment in panic disorder. This article reviews the clinical evidence for the short- and long-term efficacy and tolerability of paroxetine in panic disorder, and its effect on relapse prevention and on quality of life. The results from the short-term studies indicate that paroxetine is effective in treating panic disorder (with or without agoraphobia) either alone or in combination with cognitive-behavioural therapy. The minimum effective dose is 40 mg daily. Paroxetine was equally as effective as clomipramine in reducing the frequency of panic attacks but produced an earlier improvement in symptomatology. Continued treatment with paroxetine over periods of up to 9 months provided evidence that paroxetine maintained its anti-panic effect and prevented relapse. Paroxetine was well-tolerated during both the short- and long-term studies at doses of up to 60 mg per day. © 1997 John Wiley & Sons, Ltd.     

Antidepressants and ejaculation: a double-blind, randomized, fixed-dose study with mirtazapine and paroxetine

A double-blind, fixed-dose study in healthy men with lifelong early ejaculation was performed to evaluate potential differences in their effects on ejaculation latency, between clinically relevant doses of the selective serotonin reuptake inhibitor paroxetine and the noradrenergic and specific serotonergic antidepressant mirtazapine. Twenty-four men with an intravaginal ejaculation latency time (IELT) less than 1 minute were randomly assigned to paroxetine (20 mg/d) or mirtazapine (30 mg/d) for a period of 6 weeks; half the dosage was given in the first week. During the preceding 1-month baseline and 6-week treatment period, intravaginal ejaculation latency times were measured at home using a stopwatch procedure. The trial was completed by 18 men. Analysis of variance revealed a between-group difference in the development of the delay in intravaginal ejaculation latency time over time (P < 0.001); the intravaginal ejaculation latency time after paroxetine and mirtazapine gradually increased from 15 to 119 s and from 23 to 28 s, respectively, after 6 weeks. Paroxetine 20 mg/d exerted a strong delay (maximum 5.7-fold increase), whereas mirtazapine 30 mg/d did not delay ejaculation (0.9-fold increase). These results confirm earlier findings that paroxetine, but not mirtazapine, significantly delays orgasm and ejaculation in men with early ejaculation, whereas mirtazapine is devoid of any effect on it.     

The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study

Nonresponse to one or more antidepressants is common and an important public health problem. This study evaluated the efficacy and safety of adjunctive aripiprazole or placebo to standard antidepressant therapy (ADT) in patients with major depressive disorder who showed an inadequate response to at least 1 and up to 3 historical and 1 additional prospective ADT. The study comprised a 7-28-day screening, an 8-week prospective treatment, and a 6-week randomization phase. During prospective treatment, patients experiencing a major depressive episode (17-item Hamilton Rating Scale for Depression total score > or = 18) received single-blind adjunctive placebo plus clinicians' choice of ADT (escitalopram, fluoxetine, paroxetine controlled-release, sertraline, or venlafaxine extended-release). Subjects with inadequate response were randomized to adjunctive placebo (n = 190) or adjunctive aripiprazole (n = 191) (starting dose 5 mg/d, dose adjustments 2-20 mg/d, mean end-point dose of 11.0 mg/d). The primary efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale total score from end of prospective treatment phase to end of randomized treatment phase (last observation carried forward). Mean change in Montgomery-Asberg Depression Rating Scale total score was significantly greater with adjunctive aripiprazole than placebo (-8.5 vs -5.7; P = 0.001). Remission rates were significantly greater with adjunctive aripiprazole than placebo (25.4% vs 15.2%; P = 0.016) as were response rates (32.4% vs 17.4%; P < 0.001). Adverse events occurring in 10% of patients or more with adjunctive placebo or aripiprazole were akathisia (4.2% vs 25.9%), headache (10.5% vs 9.0%), and fatigue (3.7% vs 10.1%). Incidence of adverse events leading to discontinuation was low (adjunctive placebo [1.1%] vs adjunctive aripiprazole [3.7%]). Aripiprazole is an effective and safe adjunctive therapy as demonstrated in this short-term study for patients who are nonresponsive to standard ADT.     

A randomized, single-blind, comparison of venlafaxine with paroxetine in elderly patients suffering from resistant depression

It is estimated that up to 45% of patients with depression do not have an adequate response to a first trial of antidepressant therapy with even higher reported rates for the elderly patients. To compare the efficacy and the tolerability of venlafaxine vs. paroxetine in elderly patients suffering from resistant major depression, who did not respond to at least two previous adequate trials of antidepressants. Patients entered an 8-week single-blind study. Patients were rated using the Clinical Global Impression Scale, Hamilton Rating Scale for Depression, and the Geriatric Depression Scale. Assessments were performed at baseline and on days 7, 14, 21, 28, 42 and 56. Side effects were recorded in a systemic manner. Thirty patients were included in the study, (17 women, 13 men; mean age=75.9 years, range: 68-83) and all had completed the 6-week trial. Mean dose of venlafaxine used was 165 mg/day (SD=73.8; range 75-300 mg). Mean dose of paroxetine used was 26 mg/day (SD=15.04; range 10-60 mg). Nine patients treated with venlafaxine (60%) and five patients treated with paroxetine (33%) remitted after 8 weeks of treatment. Four patients treated with venlafaxine and eight patients treated with paroxetine failed to respond. Significant improvement in Hamilton Rating Scale for Depression scores between baseline and endpoint were observed in both groups of patients. The mean Hamilton Rating Scale for Depression change for paroxetine was -12.5 and for venlafaxine -19.1 (P<0.05). The mean Geriatric Depression Scale change for paroxetine was -3.2 and for venlafaxine -6.0 (P<0.3). The mean Clinical Global Impression Scale change was -2.3 for paroxetine and -3.5 for venlafaxine (P<0.05). Venlafaxine was significantly superior to paroxetine on Clinical Global Impression Scale and Hamilton Rating Scale for Depression measures. Side effects were transient and did not differ between treatment groups. Elderly depressed patients resistant to previous treatments had responded to a trial of paroxetine or venlafaxine. Remission rates were higher for venlafaxine and tolerability was acceptable for both compounds.     

Combined paroxetine and clonazepam treatment strategies compared to paroxetine monotherapy for panic disorder

Despite the widespread application of combined selective serotonin reuptake inhibitors (SSRI) and benzodiazepine treatment for panic disorder, there has been relatively little systematic assessment of the safety and efficacy of this therapeutic strategy. Although the limited number of studies to date suggest a more rapid onset of benefit with combined treatment, this study is the first to address the critical question of whether continued combined treatment confers superior efficacy. This study is a randomized, double-blind, three-arm study in patients with panic disorder (n = 60), comparing the efficacy and safety of paroxetine and placebo (PP), paroxetine coadministered with clonazepam followed by a tapered benzodiazepine discontinuation phase (PC-D), and ongoing combination treatment (PC-M). All treatment groups demonstrated significant improvement by endpoint. There was a significant advantage for the combined treatment groups early in treatment but, subsequently, outcome in all three groups was similar. A trend towards greater achievement of endpoint remission status for the PC-D group was attenuated when variability in baseline severity was considered. The results of this study should be interpreted in the context of a relatively moderate sample size and higher rates of early dropout. Combined treatment with paroxetine and clonazepam resulted in more rapid response than with the SSRI alone, but there was no differential benefit beyond the initial few weeks of therapy. Initiating combined treatment followed by benzodiazepine taper after a few weeks may provide early benefit while avoiding the potential adverse consequences of long-term combination therapy.     

Spotlight on paroxetine in psychiatric disorders in adults

Paroxetine is a selective serotonin reuptake inhibitor (SSRI), with antidepressant and anxiolytic activity. In 6- to 24-week well designed trials, oral paroxetine 10 to 50 mg/day was significantly more effective than placebo, at least as effective as tricyclic antidepressants (TCAs) and as effective as other SSRIs and other antidepressants in the treatment of major depressive disorder. Relapse or recurrence over 1 year after the initial response was significantly lower with paroxetine 10 to 50 mg/day than with placebo and similar to that with imipramine 50 to 275 mg/day. The efficacy of paroxetine 10 to 40 mg/day was similar to that of TCAs and fluoxetine 20 to 60 mg/day in 6- to 12-week trials in patients aged > or = 60 years with major depression. Paroxetine 10 to 40 mg/day improved depressive symptoms to an extent similar to that of TCAs in patients with comorbid illness, and was more effective than placebo in the treatment of dysthymia and minor depression. Paroxetine 20 to 60 mg/day was more effective than placebo after 8 to 12 weeks' treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder (social phobia), generalised anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Improvement was maintained or relapse was prevented for 24 weeks to 1 year in patients with OCD, panic disorder, social anxiety disorder or GAD. The efficacy of paroxetine was similar to that of other SSRIs in patients with OCD and panic disorder and similar to that of imipramine but greater than that of 2'chlordesmethyldiazepam in patients with GAD. Paroxetine is generally well tolerated in adults, elderly individuals and patients with comorbid illness, with a tolerability profile similar to that of other SSRIs. The most common adverse events with paroxetine were nausea, sexual dysfunction, somnolence, asthenia, headache, constipation, dizziness, sweating, tremor and decreased appetite. In conclusion, paroxetine, in common with other SSRIs, is generally better tolerated than TCAs and is a first-line treatment option for major depressive disorder, dysthymia or minor depression. Like other SSRIs, paroxetine is also an appropriate first-line therapy for OCD, panic disorder, social anxiety disorder, GAD and PTSD. Notably, paroxetine is the only SSRI currently approved for the treatment of social anxiety disorder and GAD, which makes it the only drug of its class indicated for all five anxiety disorders in addition to major depressive disorder. Thus, given the high degree of psychiatric comorbidity of depression and anxiety, paroxetine is an important first-line option for the treatment of major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD and PTSD.     

艾司西酞普兰治疗惊恐障碍的疗效和安全性系统评价

目的系统评价艾司西酞普兰与帕罗西汀治疗成人惊恐障碍的疗效与安全性。方法通过计算机检索及手工检索,以艾司西酞普兰（escitalopram）、帕罗西汀（paroxetine）、惊恐障碍（panicdisorder）为检索词,全面收集中国知网全文数据库（CNKI）、中国维普全文数据库（VIP）、中国生物医学文献数据库（CBMdisc）、万方全文数据库自创刊起关于艾司西酞普兰与帕罗西汀治疗惊恐障碍的临床随机对照试验（RCT）。对最终纳入的RCT按照Cochrane协作网系统评价的方法,严格评价纳入研究质量,对同质性研究采用Revfnan5．0．2软件进行统计分析。结果纳入8个RCT,共包括716名受试对象。治疗第1周、第2周和第4周末艾司西酞普兰组的有效性得分均显著高于帕罗西汀组,有统计学意义[第1周末,MD=-1．93,95％C／（-2．68,-1．19）,P=0．57;第2周末,MD=-4．6,95％C／（-6．51,-2．69）,P〈0．00001;第4周末,MD=-1．2,95％CI（-1．98,-0．43）,P=0．35）;治疗第6周和第8周后艾司西酞普兰组与帕罗西汀组的有效性差异均无统计学意义[第6周末,MD=-0．74,95％CI（-1．53,0．04）,P=0．98：第8周末,MD=-0．55,95％CI（-1．21,0．12）,P=0．72];疗程结束后的终末治愈率艾司西酞普兰组与帕罗西汀组的差异无统计学意义[RR=0．89,95％CI（0．72,1．09）,P=0．59];在分析的所有不良反应报告中,艾司西酞普兰组与帕罗西汀组所有不良反应项目差异均无统计学意义。结论艾司西酞普兰治疗成人惊恐障碍的长期疗效与帕罗西汀相当,但起效快于帕罗西汀,且具有良好的耐受性和安全性。     

Treatment of depression with comorbid anxiety disorders: differential efficacy of paroxetine versus moclobemide

To compare the efficacy and tolerability of moclobemide versus paroxetine for the treatment of depression with comorbid anxiety disorders. Outpatients fulfilling DSM-III-R criteria for major depression or dysthymia and for a co-occurring comorbid anxiety disorder (panic disorder, generalized anxiety disorder or obsessive-compulsive disorder) after a 1-week run-in phase were randomly assigned to open-label moclobemide (300-600 mg/day) or paroxetine (20-40 mg/day) for 4 months. Primary criterion for response was a 50% score reduction from baseline on Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale scores. Mean changes in Clinical Global Impressions Severity of Illness and Improvement Scales (CGI-I) were also used to evaluate treatment response. Of the 123 patients included in the study, 65 were randomly assigned to moclobemide and 58 to paroxetine. At study end, the two treatment groups did not differ significantly in terms of proportion of responders. Treatment group differences emerged when comorbid anxiety diagnoses were considered. In patients with comorbid panic disorder, paroxetine was superior to moclobemide in improving both anxiety and depression (five patients out of 18 in the moclobemide group and nine out of 14 in the paroxetine group were rated as responders according to CGI-I, P = 0.04). Neither medication was superior in treating comorbid generalized anxiety disorder. These findings indicate that both moclobemide and paroxetine are effective for treatment of depression with comorbid anxiety disorders. However, in the subgroup with comorbid panic disorder, paroxetine is more effective than moclobemide in reducing both depressive and anxiety symptoms.     

Standard and higher dose of olanzapine in patients with schizophrenia or schizoaffective disorder: a randomized, double-blind, fixed-dose study

The objective of this study was to assess the dose-response relationship of standard and higher doses of olanzapine in a randomized, double-blind, 8-week, fixed-dose study comparing olanzapine 10 (n = 199), 20 (n = 200), and 40 mg/d (n = 200) for patients with schizophrenia or schizoaffective disorder and suboptimal response to current treatment. Patients meeting criteria for antipsychotic treatment resistance were excluded. Dose-response relationship was assessed by linear regression analysis with log-transformed dose (independent variable) and Positive and Negative Syndrome Scale (PANSS) total score (dependent variable). There were no significant dose group differences in patients completing the study (overall, 67.8%). All dose groups showed statistically significant improvement in PANSS total scores from baseline to end point without significant dose-response relationship (P = 0.295). Post hoc analysis of response showed significant interaction between baseline PANSS and dose (P = 0.023), indicating better response at higher doses for patients with higher baseline PANSS. There was a significant dose response for mean change in weight (P = 0.003) with significant difference between the 10- and 40-mg-dose groups (P = 0.002; 1.9 [10 mg/d], 2.3 [20 mg/d], and 3.0 kg [40 mg/d]). There was a significant dose response for change in prolactin (P < 0.001) with a significant difference between each group (-10.5 [10 mg/d], -1.7 [20 mg/d], and 4.9 ng/mL [40 mg/d]; P < or = 0.018). Over 8 weeks, non-treatment-resistant patients with schizophrenia or schizoaffective disorder responded to all 3 doses of olanzapine, without a statistically significant dose-response relationship, suggesting that for many patients with schizophrenia or schizoaffective disorder, particularly those who are mildly or moderately ill, 10 mg/d should be the initial dose of choice.     

A randomized, double-blind, parallel-group, fixed-dose, clinical trial of quetiapine at 600 versus 1200 mg/d for patients with treatment-resistant schizophrenia or schizoaffective disorder

Quetiapine is often prescribed at doses higher than those approved by regulatory authorities, with limited evidence from controlled trials. The objective of this study was to assess the safety, tolerability, and efficacy of high-dose quetiapine (1200 mg/d) compared with a standard dose of 600 mg/d among patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, schizophrenia or schizoaffective disorder hospitalized at 2 state-operated psychiatric facilities. In order to be eligible for randomization, subjects were required to prospectively fail to demonstrate an initial therapeutic response during a 4-week run-in phase with quetiapine at 600 mg/d (immediate release and dosed twice a day). Lack of an adequate initial response was defined a 15% or lower decrease in the Positive and Negative Syndrome Scale total score. Patients were then randomized to either continue quetiapine at 600 mg/d for an additional 8 weeks or to receive 1200 mg/d quetiapine instead. No significant differences were observed between the high dose (n = 29) and standard dose (n = 31) groups in change from baseline to endpoint on extrapyramidal symptoms, electrocardiographic changes, or most laboratory measures between groups. There was a significant difference between groups for triglycerides (P = 0.035), and post hoc tests revealed a decrease in triglycerides from baseline (mean [SD], 162.7 [59.3] mg/dL) to endpoint (mean [SD], 134.8 [62.7] mg/dL) for the 600 mg/d group (P = 0.019). The mean change in the Positive and Negative Syndrome Scale total score did not differ between groups. In conclusion, quetiapine at 1200 mg/d, although reasonably tolerated, did not confer any advantages over quetiapine at 600 mg/d among patients who had failed to demonstrate an adequate response to a prospective 4-week trial of 600 mg/d.     

A randomized, multicenter, double-blind, placebo-controlled study of the efficacy and safety of aripiprazole for the treatment of alcohol dependence

The purpose of this study was to compare the efficacy and safety of aripiprazole with placebo in the treatment of alcoholics. In this 12-week multicenter, double-blind study, 295 patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition alcohol dependence were randomized to treatment with aripiprazole (initiated at 2 mg/d, titrated to a maximum dose of 30 mg/d at day 28) or placebo after screening, wherein patients maintained alcohol abstinence for 3 days or more. The primary efficacy measure was the percentage of days abstinent over 12 weeks. Discontinuations (40.3% vs 26.7%) and treatment-related adverse events (82.8% vs 63.6%) were higher with aripiprazole than with placebo. Mean percentage of days abstinent was similar between aripiprazole and placebo (58.7% vs 63.3%; P = 0.227). Percentage of subjects without a heavy drinking day and the time to first drinking day were also comparable between groups, although the aripiprazole group had fewer drinks per drinking day (4.4 vs 5.5 drinks; P < 0.001). The aripiprazole group showed a larger decrease in percent carbohydrate-deficient transferrin, a biomarker of heavy alcohol consumption at weeks 4 (-14.91% vs -2.23%; P = 0.020) and 8 (-16.92% vs -5.33%; P = 0.021), although not at week 12 (-9.06% vs -4.12%; P = 0.298). At study end point, aripiprazole-treated subjects reported more positive subjective treatment effects and less overall severity of alcohol dependence than placebo-treated subjects. Although there was no difference between aripiprazole and placebo on the primary end point, possibly because of dose-related attrition, effects on the secondary outcomes suggest that further study of aripiprazole for treatment of alcohol dependence may be warranted at lower doses.     

Once-daily high-dose pindolol for paroxetine-refractory premature ejaculation: a double-blind, placebo-controlled and randomized study

PURPOSE: To evaluate the efficacy and safety of pindolol 7.5 mg/d in delaying of ejaculation in paroxetine-refractory patients. MATERIALS AND METHODS: Eighty-six married men (mean age, 33 years) with premature ejaculation unresponsive to paroxetine 20 mg/d given for 2 months or longer were randomized to receive 7.5 mg pindolol (n = 44) (group 1) (PXT + POL) or placebo (n = 42) (group 2) (PXT + PBO) for 6 weeks, while continuing paroxetine. After 6 weeks, all patients received paroxetine and placebo and were followed for 3 further weeks in a single-blind manner. Pretreatment evaluation included history and physical examination, mean intravaginal ejaculatory latency time (IELT), International Index of Erectile Function (IIEF), and Meares-Stamey test. The efficacy of 2 treatments was assessed every 1 week during treatment and, at the end of study, using responses to IIEF, IELT evaluation, mean intercourse satisfaction domain, mean weekly coitus episodes, and adverse drug effects. RESULTS: Seventy-seven (89.5%) completed the whole treatment schedule. At the end of 6-week treatment period, the IELT after paroxetine-pindolol and paroxetine-placebo gradually increased from mean 48 and 41 seconds to approximately 188 and 58 seconds, respectively (P = 0.001). The mean weekly intercourse episodes increased from pretreatment values of 1.5 and 1.5 to 2.7 and 1.7, for groups PXT + POL and PXT + PBO, respectively (P = 0.01). Baseline mean intercourse satisfaction domain values of IIEF 12 and 11 reached to 16 and 11 at 6-week treatment in PXT + POL and PXT + PBO groups, respectively (P = 0.01). Upon discontinuing pindolol, all outcome measures returned to baseline values rapidly. The incidence of side effects with paroxetine-pindolol was significantly higher (P = 0.04). CONCLUSIONS: These findings support that a single high dose of pindolol (7.5 mg) is an effective augmentation strategy in paroxetine-refractory patients.     

Influence of clonazepam and carbamazepine on alcohol withdrawal syndrome, preference and development of tolerance to ethanol in rats.

The effects of clonazepam (0.3 and 1.0 mg/kg or 0.1 mg/kg, b.i.d., 5 days) and carbamazepine (50 and 100 mg/kg or 12.5 and 50 mg/kg b.i.d., 5 days) on alcohol withdrawal syndrome in rats were investigated. Moreover, the influence of clonazepam (0.3 mg/kg, single dose, or repeated doses for 8 days) and carbamazepine (50 mg/kg, single dose, or repeated doses for 8 days) on the development of tolerance to ethanol was also examined. To study the influence of clonazepam and carbamazepine on preference to ethanol, both drugs were administered for 5 days during the last week of the experiment, (clonazepam at 0.1 mg/kg, b.i.d., i.p. and carbamazepine at 12.5 mg/kg, b.i.d, i.p.). Clonazepam and carbamazepine administered at single doses as well as multiple doses diminished the symptoms of withdrawal syndrome. Clonazepam did not prevent the development of tolerance to sleep-inducing and hypothermal action of ethanol, while carbamazepine prevented the development of tolerance to hypnotic effect of ethanol. Carbamazepine clearly reduced preference to ethanol (significantly vs. the control group and vs. the baseline values). Clonazepam also diminished preference to alcohol, but only in comparison with baseline values.     

Dose-dependent interaction of paroxetine with risperidone in schizophrenic patients

Augmentation with paroxetine (10-40 mg/d) for antipsychotic treatment may improve the negative symptoms in schizophrenic patients but involves a risk of drug-drug interaction. We studied the effects of paroxetine on plasma concentrations of risperidone and 9-hydroxyrisperidone and their clinical symptoms in risperidone-treated patients. Twelve schizophrenic inpatients with prevailingly negative symptoms receiving risperidone 4 mg/d were, in addition, treated with incremental doses of paroxetine for 12 weeks (10, 20, and 40 mg/d for 4 weeks each). Plasma concentrations of risperidone and 9-hydroxyrisperidone were quantified with liquid chromatography-mass spectrometry mass-mass spectrometry together with clinical assessments before and after each phase of the 3 paroxetine doses. Risperidone concentrations during coadministration of paroxetine 10, 20, and 40 mg/d were 3.8-fold (95% confidence interval, 3.2-5.8, P < 0.01), 7.1-fold (95% confidence interval, 5.3-16.5, P < 0.01), and 9.7-fold (95% confidence interval, 7.8-22.5, P < 0.01) higher than that before paroxetine coadministration, respectively. Active moiety (risperidone plus 9-hydroxyrisperidone) concentration was not increased during the paroxetine 10 mg/d (1.3-fold, not significant) or 20 mg/d (1.6-fold, not significant), but were significantly increased by 1.8-fold (95% confidence interval, 1.4-2.7, P < 0.05) during the paroxetine 40 mg/d. Significant improvement in negative symptoms was observed from 10 to 40 mg/d of paroxetine, whereas scores in extrapyramidal side effects during 20 and 40 mg/d of paroxetine were significantly higher than baseline score. This study indicates that paroxetine increases plasma risperidone concentration and active moiety concentration in a dose-dependent manner. Low-dose coadministration of paroxetine with risperidone may be safe and effective in the treatment of schizophrenic patients with negative symptoms.     

High plasma concentrations of paroxetine impede clinical response in patients with panic disorder

Selective serotonin reuptake inhibitors are thought to interact with serotonergic neurons and be effective for treatment of panic disorder. In the present study, the authors investigated an association between plasma concentrations of paroxetine in patients with panic disorder and clinical response to initial treatment with paroxetine. Subjects were 21 unrelated Japanese patients who fulfilled DSM-IV-TR criteria for a diagnosis of panic disorder (6 males, 15 females, mean age 35.9 +/- 11.3 years). Subjects were administered 10 mg/day of paroxetine for 2 weeks as initial treatment. Improvement of the symptoms of the disorder was assessed with the Panic and Agoraphobia Scale (PAS). In the range of plasma levels >20 ng/mL, none of the subjects showed the reduction ratio in PAS score >0.2. The subjects whose plasma concentrations of paroxetine were less than 20 ng/mL had a significantly higher mean reduction ratio in PAS score than the subjects whose plasma concentrations of paroxetine were >20 ng/mL. Multiple regression analysis showed that the plasma concentration of paroxetine was the only significant factor and accounted for 28.0% of the variability in the reduction ratio of PAS score of the subjects. The final model of correlation was: reduction ratio in PAS score = 0.423 - 0.009 x (plasma concentrations of paroxetine) (R = 0.529, P = 0.014, coefficient of determination (R2) = 0.280). Assuming that the reduction ratio in PAS score was 0.2 in the equation above, plasma concentration of paroxetine is calculated to be about 25 ng/mL, which is suggested to be the upper end of the therapeutic window for the initial phase of the treatment with paroxetine for panic disorder.     

SSRIs and ejaculation: a double-blind, randomized, fixed-dose study with paroxetine and citalopram.

Selective serotonin reuptake inhibitors (SSRIs) are known to induce delayed orgasm and ejaculation. However, different SSRIs may differentially delay ejaculation. A double-blind, fixed-dose study in healthy men with lifelong rapid ejaculation was performed to evaluate potential differences between clinically relevant doses of two selective serotonin reuptake inhibitors, paroxetine and citalopram, in their effects on ejaculation. Thirty men with an intravaginal ejaculation latency time (IELT) less than 1 minute were randomly assigned to receive paroxetine (20 mg/day) and citalopram (20 mg/day) for 5 weeks, after taking half the dosage in the first week. During the 1-month baseline and 6-week treatment period, IELTs were measured at home by using a stopwatch procedure. The trial was completed by 23 men. Analysis of variance revealed a between-group difference in the evolution of IELT delay over time (p = 0.0004); the IELT after paroxetine and citalopram gradually increased from 18 and 21 seconds to approximately 170 and 44 seconds, respectively. Paroxetine 20 mg/day exerted a strong delay (8.9-fold increase), whereas citalopram 20 mg/day mildly delayed ejaculation (1.8-fold increase). These results indicate that paroxetine leads to a significant delay in orgasm and ejaculation, whereas citalopram seems to have less of an effect on it.     

帕罗西汀联合针刺治疗难治性强迫症的对照研究

目的 探讨针刺治疗难治性强迫症患者的临床效果和安全性.方法 将60例难治性强迫症患者随机分为研究组(帕罗西汀+针刺,n=30)和对照组(帕罗西汀,n=30)进行治疗,疗程为8周.采用耶鲁-布朗强迫症状评定量表(Y-BOCS)、汉密尔顿抑郁量表(HAMD)评价两组疗效;采用副作用量表(TESS)评价两组安全性.结果 研究组和对照组有效率分别为80.0％和66.7％,差异有统计学意义(P＜0.05);治疗后,研究组Y-BOCS、HAMD评分下降更明显(P＜0.01);两组在治疗过程中出现的副作用比较,差异无统计学意义(P＞0.05).结论 针刺合并帕罗西汀治疗难治性强迫症可提高疗效,且安全性好,值得进一步推广应用.