Antiparkinsonian agents and long-term neuroleptic treatment. Effect of G 31.406, orphenadrine, and placebo on parkinsonism, schizophrenic symptoms, depression and anxiety.

The need for medication with anticholinergic antiparkinsonian drugs was examined in 118 schizophrenic patients under long-term neuroleptic treatment. It was found that 1) none of 18 patients under treatment with low mg potency neuroleptics (chlorprothixene, clozapine, and thioridazine) had any need for anticholinergics; 2) of 60 patients under treatment with short-acting high mg potency neuroleptics (perphenazine greater than 16 mg daily and haloperidol greater than 2 mg daily) nine patients (15%) required medication with anticholinergics, whereas 3) of 40 patients under treatment with long-acting (depot) neuroleptics, 17 (43%) had a need for anticholinergic medication; and 4) no patient factors predisposing to the need for continued antiparkinsonian treatment could be identified. In an additional double-blind cross-over study of 12 patients presenting persisting neuroleptic-induced parkinsonism, it was found that G 31.406 (a new potentially antiparkinsonian drug), compared with placebo, had an antiparkinsonian effect (P less than 0.01) as well as an antidepressant effect (P less than 0.05). G 31.406 resulted in an improvement in anxiety and schizophrenia-score in some patients. Compared with placebo, orphenadrine had a more questionable effect on parkinsonism (0.05 less than P less than 0.01) and no significant effect on mental symptoms. There were no significant differences between the effects of G 31.406 and orphenadrine.     

Prophylactic therapy with lithium in elderly patients with unipolar major depression

OBJECTIVES: To compare the relapse rate of elderly depressed patients taking low dose lithium as an additional therapy with antidepressant medication to those receiving antidepressant medication alone. METHODS: Fifty elderly subjects recovering from a major depressive illness taking continuation antidepressants were randomised, in a double blind study, to receive additional lithium carbonate or placebo and followed up over a two year period for evidence of relapse. RESULTS: Relapse rate was significantly greater in those subjects taking antidepressant medication alone compared to subjects taking additional lithium therapy. After six months four (17%) subjects taking antidepressant medication alone had relapsed, whereas none of the subjects taking additional lithium had relapsed. After two years eight (33%) subjects taking antidepressant medication alone had relapsed, whereas only one (4%) of the subjects taking additional lithium had relapsed. CONCLUSION: This preliminary study suggests that long-term low dose lithium therapy is well tolerated and protects elderly patients from a relapse of depressive illness.     

Effects of pill-giving on maintenance of placebo response in patients with chronic mild depression

Fifty outpatients with mild, chronic, mood-reactive depression whose mood improved markedly after a 10-day single-blind placebo trial were randomly assigned in a double-blind design either to have their placebo medication discontinued or to have it maintained for an additional 6 weeks. Half of the patients in each condition relapsed within 6 weeks, indicating that pill-taking itself does not influence maintenance of placebo response. Placebo response was more likely to be maintained in patients who were currently married. At the end of 3 months, the overall relapse rate was 58%. The authors raise questions about the utility of the initial 10-day placebo washout in antidepressant clinical trials, and they discuss limits on the generalizability of their findings.     

Biperiden withdrawal in schizophrenic inpatients receiving long-term antipsychotic medication

In a double-blind, 4 week study, 42 chronic schizophrenic inpatients receiving antipsychotic and antiparkinsonian (AP) drugs for greater than 3 months were either switched to placebo or maintained on biperiden. In the majority of the patients no clinically apparent discomfort was observed, and only two of 21 placebo patients developed extrapyramidal side effects (EPS) severe enough to require resumption of AP therapy. No significant increase was shown in most items on EPS. Our data suggest that for the majority of patients on long-term AP medication AP drugs should be prescribed only when EPS develop.     

Management of depression relapse: re-initiation of duloxetine treatment or dose increase

Continuation of antidepressant therapy after patients have responded to medication has been shown to greatly reduce but not eliminate relapse. We evaluated response to reinstating or increasing drug doses in patients who relapsed during a long-term, randomized, double-blind, continuation phase study of duloxetine treatment for major depressive disorder (MDD). Patients with HAMD17 scores of >18 and CGI-Severity scores of >4 received duloxetine 60 mg QD for 12 weeks, responders then received 26 weeks of duloxetine 60 mg QD or placebo. The relapsing patients who started 12 weeks of rescue treatment received duloxetine 60 mg QD (if relapsing on placebo) or duloxetine 60 mg BID (if relapsing on duloxetine). In the continuation phase, 87 patients received duloxetine 60 mg QD (n=58) or 60 mg BID (n=29) as treatment for relapse. The percentage of patients who responded to treatment after relapse was 62% of those whose dose was increased from 60 mg QD to 60 mg BID, and 74% for those who switched from placebo to duloxetine 60 mg daily. By the end of the study, 32 patients taking duloxetine 60 mg QD were in remission (57%), compared with 11 patients taking duloxetine 60 mg BID (38%). There was significant improvement in HAMD17 and CGI-Severity scores for both groups at endpoint vs. start of treatment for relapse. Significant improvements were seen for all visual analog scale parameters in the 60 mg QD group, but only Interference with Daily Activities and Back Pain parameters showed significant improvement for patients receiving 60 mg BID. Significant within-group improvement from baseline was seen for both groups in Symptom Questionnaire-Somatic Subscale total and pain subscales. Treatment-emergent adverse events were mild/moderate in severity; no clinically significant changes were noted in laboratory results or vital signs. Reinstatement of duloxetine 60 mg QD was effective for patients who relapsed after discontinuing drug. Patients relapsing on duloxetine 60 mg QD benefited from an increase to 60 mg BID. These duloxetine doses were well tolerated and effective, and appear appropriate for MDD patients requiring treatment of relapse.     

Predictors of relapse in a prospective study of fluoxetine treatment of major depression

OBJECTIVE: Loss of response to a previously effective antidepressant is a common clinical problem. Retrospective analyses have shown that the pattern of response during antidepressant treatment (late onset and persistent versus other patterns) can be used to predict relapse during continuation and maintenance treatment and possibly to identify placebo responses to treatment. This study was designed to test the predictive value of response pattern prospectively and to examine the data for other predictors of relapse. METHOD: Five hundred seventy persons with major depressive disorder were treated with fluoxetine for 12 weeks and their pattern of response was determined. Those who responded (N=292) underwent random assignment, under double-blind conditions, to continue taking fluoxetine or to switch to placebo for 52 weeks or until relapse. Survival analysis was used to examine the effect of covariates on relapse. RESULTS: Although fluoxetine was significantly more effective than placebo during maintenance treatment, this chronically ill group had a high rate of relapse. Contrary to previous findings, a pattern of acute response was not predictive of relapse. Chronicity, symptom severity, a neurovegetative symptom pattern, and female gender were all associated with a significantly greater risk of relapse, with no difference observed between fluoxetine and placebo. CONCLUSIONS: The pattern of response to acute treatment appears to be inconsistently predictive of relapse. There is a high rate of relapse with both active medication and placebo in patients with chronic depression. Illness characteristics predict loss of response both to fluoxetine and to placebo. No variable examined was predictive of differential relapse rates between fluoxetine and placebo.     

Long-term outcome of antidepressant treatment for bulimia nervosa

OBJECTIVE: The purpose of this study was 1) to replicate previous work indicating that antidepressant medication is superior to placebo in the treatment of bulimia nervosa and 2) to assess the long-term efficacy of this form of treatment. METHOD: Eighty patients entered a three-phase treatment protocol. An 8-week double-blind initiation phase was used to compare the effects of desipramine and placebo. Patients who responded satisfactorily to desipramine entered a 16-week maintenance phase. Patients who remained well were then randomly assigned to either desipramine or placebo for 6 additional months (discontinuation phase). The primary outcome measure was binge frequency, which was assessed weekly by self-report diaries. RESULTS: In the initiation phase the superiority of desipramine over placebo in reducing binge frequency was demonstrated. Patients treated with desipramine had a mean reduction in binge frequency of 47% at termination, whereas patients taking placebo experienced a mean increase of 7%. Less than half of the patients treated with desipramine met the criteria for entering the maintenance phase, and 29% of the patients entering that phase relapsed in the following 4 months. There were not enough patients in the discontinuation phase to permit clear conclusions about the need for continued antidepressant medication after 6 months of treatment. CONCLUSIONS: The study documents a beneficial effect of desipramine in the treatment of bulimia nervosa when compared to placebo. However, limited improvement and considerable relapse with continued treatment suggest serious limitations to the long-term efficacy of a single antidepressant trial in treating bulimia nervosa.     

Drug levels and antiparkinsonian drugs in neuroleptic-treated schizophrenic patients

The limitations of antiparkinsonian treatment strategy when using anticholinergic drugs are determined by their side effects induced through excessive inhibition of parasympathetic functions. In the present study we have investigated the peripheral effects of antiparkinsonian agents on blood levels of concomitantly administered neuroleptic drugs. We have compared the anticholinergic and a dopamine mimetic antiparkinsonian agent in their effects on serum neuroleptic activity (SNA) and serum anticholinergic activity (SAA). Sixteen schizophrenic patients on chronic neuroleptic therapy with steady state neuroleptic levels were receiving either amantadine, 200 mg/day, or anticholinergic drugs (trihexyphenidyl, 10 mg/day, or benztropine, 6 mg/day) for the first 2 weeks, after which the amantadine group was crossed over to anticholinergic and the anticholinergic group to amantadine for the following 2 weeks. Blood samples were obtained once a week along with clinical testing. The results indicate that SAA was fivefold higher with benztropine than with trihexyphenidyl and that amantadine had no effect on SAA. Moreover, SNA was not altered either by anticholinergics or amantadine coadministration, indicating that the therapeutic blood neuroleptic levels are not compromised by antiparkinsonian administration.     

Carbamazepine as an adjunct of antipsychotic therapy

The effect of low-dose haloperidol combined with the anticonvulsant carbamazepine was investigated in a 5-week placebo-controlled, double-blind study in acute schizophrenic patients. Weekly ratings showed a clinically pronounced and statistically significant improvement in both the carbamazepine and placebo groups. However, the patients on carbamazepine needed less neuroleptic and anticholinergic medication and experienced fewer side effects compared to the patients on placebo. Moreover, patients in the carbamazepine group showed a clear deterioration after discontinuation of carbamazepine (but maintenance of neuroleptic medication), while the placebo group did not change after discontinuation of placebo. Concomitant treatment with carbamazepine in psychotic patients may help to reduce neuroleptic dosages and unwanted side effects.     

Withdrawal of trihexyphenidyl

Trihexyphenidyl, a synthetic anticholinergic, used to control extrapyramidal symptoms arising from neuroleptic drug therapy has been a subject of controversy regarding the need for continuous antiparkinsonian therapy. In a group of 22 psychiatric patients receiving long-term antipsychotic medication concurrently with trihexyphenidyl the effects of trihexyphenidyl withdrawal were studied double-blind and placebo controlled. Anxiety, psychotic symptoms, extrapyramidal symptoms and salivary flow were monitored. Blood pressure, pulse, sleep duration, weight and body temperature were recorded daily. The result was a recognizable withdrawal syndrome indicated by an increase in anxiety with various physical complaints, as well as evidence of orthostatic hypotension and tachycardia. A temporary deterioration was noted in psychotic symptomatology and extrapyramidal symptoms. The majority of the parameters regained baseline values, indicating the symptoms were related to the discontinuation of trihexyphenidyl and supporting the existence of a withdrawal syndrome.     

Evaluation of the need for prophylactic antiparkinsonian medication in psychotic patients treated with neuroleptics

A double-blind study of 42 psychotic patients treated with neuroleptics evaluated the need for prophylactic use of antiparkinsonian medication. The patients assigned to placebo (N = 27) presented significantly more severe extrapyramidal symptomatology, particularly dystonias, than those given trihexyphenidyl (N = 15), indicating a need for the prophylactic use of antiparkinsonian medication during treatment with neuroleptics.     

Relapse following combined treatment discontinuation in a placebo-controlled trial for panic disorder

A recent double-blind, placebo-controlled trial (Barlow et al., 2000 JAMA. 283:2529-2536) examined separate and synergistic effects of psychological and pharmacological treatments for panic disorder. One finding warranting further investigation involved relatively high relapse rates of participants who received cognitive-behavioral therapy (CBT) + imipramine when compared with those receiving CBT + placebo. In this article, we investigate why CBT was less effective in protecting against relapse for individuals in the active drug condition. We hypothesized that participants correctly deduced treatment assignments and, for those taking imipramine, this was associated with the belief that they were no longer taking active drug after discontinuation, accounting for increased relapse rates. Contrary to hypothesis, there were no group differences in frequencies of guessing drug or placebo, nor were specific beliefs about taking drug or placebo differentially associated with relapse. Other possible reasons for differential relapse rates and treatment implications are discussed.     

Acute and long-term treatment and prevention of relapse of obsessive-compulsive disorder with paroxetine

BACKGROUND: Limited information is available regarding optimal dosing or long-term pharmacotherapy with serotonin reuptake inhibitors in obsessive-compulsive disorder. This study evaluated the acute safety and efficacy and long-term efficacy, safety, and impact on relapse prevention of paroxetine in obsessive-compulsive disorder. METHOD: We enrolled 348 outpatients with DSM-III-R obsessive-compulsive disorder in phase 1, a 12-week randomized, double-blind, parallel study of fixed doses of paroxetine (20 mg/day, 40 mg/day, or 60 mg/day) and placebo. In phase 2, 263 phase 1 completers were enrolled in 6 months of flexibly dosed open-label paroxetine treatment. In phase 3, 105 responders to open-label paroxetine were randomized to 6-month double-blind, fixed-dose, parallel paroxetine/placebo treatment to evaluate long-term efficacy, safety, and impact on relapse prevention. The study was conducted from July 1991 to February 1994. RESULTS: Patients in phase 1 acute treatment receiving 40 mg/day or 60 mg/day of paroxetine improved significantly (p < .05) more than those receiving placebo; the mean reduction in Yale-Brown Obsessive-Compulsive Scale score was 25% on 40 mg/day of paroxetine and 29% on 60 mg/day compared with 13% on placebo. During phase 3, long-term treatment, a greater proportion of placebo- (59%) than paroxetine-treated (38%) patients relapsed. Paroxetine was well tolerated at all doses, with no significant increase in frequency of adverse events during long-term compared with short-term therapy. Greater adverse events in the placebo than in the paroxetine group in phase 3 probably represent a discontinuation effect. CONCLUSION: Paroxetine doses of 40 mg/day and 60 mg/day (but not 20 mg/day) are effective in treating acute obsessive-compulsive disorder. Long-term treatment with paroxetine is effective and safe, decreases the rate of relapse, and lengthens the time to relapse.     

Ropinirole is effective in the long-term management of restless legs syndrome: a randomized controlled trial.

The objective of this study was to investigate the long-term efficacy of ropinirole in patients with restless legs syndrome (RLS) and to assess the potential for relapse after the discontinuation of active treatment. Patients with primary RLS (n = 202) received single-blind ropinirole for 24 weeks. Patients meeting treatment continuation criteria were randomized to double-blind treatment with ropinirole or placebo for a further 12 weeks. The primary efficacy variable was the proportion of patients relapsing during double-blind treatment. Additional efficacy measures included time to relapse, withdrawals due to lack of efficacy, improvement on the Clinical Global Impression-Improvement (CGI-I) scale, change in International Restless Legs Scale (IRLS) score during double-blind treatment, and changes in sleep and quality of life (QoL) parameters. Significantly fewer patients relapsed on ropinirole than on placebo (32.6% vs. 57.8%; P = 0.0156). Time to relapse was longer with ropinirole and more patients withdrew due to lack of efficacy with placebo. Patients showed improvements in IRLS and CGI-I scores, sleep and QoL parameters with single-blind ropinirole, which were better maintained when ropinirole was continued during the double-blind phase, but reduced with placebo. Ropinirole was well tolerated; adverse events were typical for dopamine agonists. Ropinirole was highly effective and well tolerated in the long-term management of RLS, with pharmacological effect over 36 weeks.     

Escitalopram prevents relapse in older patients with major depressive disorder.

OBJECTIVE: The present study investigated the efficacy and tolerability of escitalopram in the prevention of relapse of major depressive disorder (MDD) in older patients who had responded to acute treatment with escitalopram. METHOD: A total of 405 patients who were aged 65 years or older with a primary diagnosis of MDD (according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) and a Montgomery-Asberg Depression Rating Scale (MADRS) total score of 22 or more received 12-week, open-label escitalopram 10 or 20 mg per day treatment. Remitters (MADRS 相似文献   

Changes in brain function of depressed subjects during treatment with placebo.

OBJECTIVE: It has been proposed that 50%-75% of the efficacy of antidepressant medication represents the placebo effect, since many depressed patients improve when treated with either medication or placebo. This study examined brain function in depressed subjects receiving either active medication or placebo and sought to determine whether quantitative electroencephalography (QEEG) could detect differences in brain function between medication and placebo responders. Both QEEG power and cordance, a new measure that reflects cerebral perfusion and is sensitive to the effect of antidepressant medication, were examined. METHOD: Fifty-one subjects with major depression were enrolled in one of two independent, 9-week double-blind, placebo-controlled studies in which either fluoxetine (N=24) or venlafaxine (N=27) was the active medication. Serial QEEG recordings were performed during the course of treatment. After 9 weeks, the blind was broken and subjects were classified as medication responders, placebo responders, medication nonresponders, or placebo nonresponders. RESULTS: No significant pretreatment differences in clinical or QEEG measures were found among the four outcome groups. Placebo responders, however, showed a significant increase in prefrontal cordance starting early in treatment that was not seen in medication responders (who showed decreased cordance) or in medication nonresponders or placebo nonresponders (who showed no significant change). There was no significant change in QEEG power during treatment. CONCLUSIONS: These findings suggest that "effective" placebo treatment induces changes in brain function that are distinct from those associated with antidepressant medication. If these results are confirmed, cordance may be useful for differentiating between medication and placebo responders.     

Double-blind, single-dose, cross-over study of the effects of pramipexole, pergolide, and placebo on rest tremor and UPDRS part III in Parkinson's disease.

Tremor is one of the cardinal signs of Parkinson's disease (PD) but its response to antiparkinsonian medication is variable. It has been postulated that pramipexole may have a stronger antiparkinsonian tremor effect than pergolide, another direct acting dopamine agonist medication, possibly because the former has preferential affinity for the dopamine D3 receptor. The purpose of this pilot study was to compare the effects of a single oral dose of either pramipexole (Pr) or pergolide (Pe) or placebo (Pl) on parkinsonian tremor and the motor (part III) subsection of the UPDRS. Ten patients (6 men, 4 women), mean age 65.3 years, mean duration from diagnosis of 2.6 years, with tremor dominant PD were recruited. On three separate occasions a single dose of pramipexole (salt) 500 microg, pergolide 500 microg or placebo were administered in random order to each patient, who were pretreated with domperidone and had their antiparkinsonian medication withheld from midnight before study. After each medication patients were assessed at baseline and then every 30 min for 4 hr using a 0 to 10 tremor rating scale and the UPDRS (part III) in a double-blind protocol. Adverse effects were systematically recorded. The results demonstrate that 500 microg of either pramipexole or pergolide reduced PD rest tremor scores to a similar degree, which at peak effect was significantly greater than placebo (respectively Pe v Pl: P < 0.006, Pr v Pl: P < 0.033). The two active drugs also had weaker beneficial effects on the UPDRS part III. Pergolide, however, was significantly more likely than pramipexole to cause nausea (P = 0.005) or vomiting (P = 0.014).     

Efficacy and tolerability of paroxetine for the long-term treatment of generalized anxiety disorder

BACKGROUND: Paroxetine has demonstrated efficacy in depression and anxiety disorders, including generalized anxiety disorder (GAD). This 32-week study evaluated the maintained efficacy and safety of paroxetine in GAD by assessing the potential for relapse after discontinuation of medication. METHOD: Adults (N = 652) with DSM-IV GAD and a Clinical Global Impressions-Severity of Illness (CGI-S) score > or = 4 received paroxetine (20-50 mg/day) for 8 weeks. Patients whose CGI-S score had decreased by at least 2 points to < or = 3 at week 8 were randomly assigned to double-blind treatment with paroxetine (N = 278) or placebo (N = 288) for a further 24 weeks. The primary efficacy parameter was the proportion of patients relapsing (an increase in CGI-S score of at least 2 points to a score < or = 4 or withdrawal resulting from lack of efficacy) during double-blind treatment. RESULTS: Significantly fewer paroxetine than placebo patients relapsed during the 24-week double-blind phase (10.9% vs. 39.9%; p <.001). Placebo patients were almost 5 times more likely to relapse than paroxetine patients (estimated hazard ratio = 0.213 [95% CI = 0.1 to 0.3]; p <.001). Statistical significance in favor of paroxetine was demonstrated for all secondary efficacy parameters, including functional status. Twice as many paroxetine patients as placebo patients (73%) achieved remission. Paroxetine was well tolerated, with no unexpected adverse events reported. CONCLUSION: Paroxetine was found to be effective and well tolerated for both the short- and long-term treatment of DSM-IV GAD. Continued treatment with paroxetine significantly reduced the potential for relapse of GAD symptoms.     

Usefulness of Antiparkinsonian Drugs during Neuroleptic Treatment and the Effect of Clonazepam on Akathisia and Parkinsonism Occurred after Antiparkinsonian Drug Withdrawal: A Double-Blind Study

Abstract: Antiparkinsonian drugs used for 117 : chronic schizophrenic patients receiving long-term neuroleptic treatment were withdrawn. Seventy-eight (66.7%) of the 117 : patients were without akathisia and/or parkinsonism at least for 6 : weeks after the antiparkinsodan drug withdrawal. A double-blind study of clonazepam was carried out for 22 : patients and clonazepam was effective on 8 : patients (100%) with akathisia and on 3 : patients (75%) with parkinsonism. The authors conclude that these data support the need for discontinuous use of antiparkinsonian medication during the long-term neuroleptic therapy of chronic schzophrenic patients and the effectiveness of clonazepam in managing antiparkinsonian drug withdrawal-induced akathisia and parkinsonism.     

A prospective 3-year longitudinal study of cognitive predictors of relapse in first-episode schizophrenic patients

BACKGROUND: Cognitive predictors of relapse have been extensively explored only in few long term longitudinal studies of first-episode schizophrenia. METHOD: This study prospectively followed 93 patients with first-episode schizophrenia, schizophreniform disorder, and schizoaffective disorder for 3 years after their first-episode illness. Cognitive domains including verbal intelligence, verbal and visual memory, verbal fluency, and Wisconsin Card Sorting Test performance were investigated as potential predictors of relapse. RESULTS: We found that by the first year 21% patients had relapsed, by the second year 33% had relapsed, and by the third year 40% had relapsed. There was a significant difference in the relapse rate between patients with good adherence and patients with poor adherence to medication regimes. A multiple logistic regression analysis revealed that after controlling for medication adherence, perseverative error in the Wisconsin Card Sorting Test was the only cognitive function that significantly predict relapse with an odds ratio of 2.4. CONCLUSIONS: Cognitive flexibility in set shifting is related to tendency towards relapse in first-episode schizophrenic patients. Other cognitive factors appear not to be related to relapse. Possible mechanisms included the link between prefrontal dysfunction and sub-cortical dopamine system stability, as well as the effects of executive dysfunction on insight impairment and adherence behavior.