Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: A multicentre, randomised, double-blind controlled trial.

Previous randomised placebo-controlled trials with low-to-medium doses of baclofen (30-60mg) showed inconsistent results, but case studies suggested a dose-response effect and positive outcomes in patients on high doses of baclofen (up to 270mg). Its prescription was temporary permitted for the treatment of alcohol dependence (AD) in France, and baclofen is now widely prescribed. Recently, a small RCT found a strong effect of a mean dose of 180mg baclofen. In the present study the efficacy and safety of high doses of baclofen was examined in a multicentre, double-blind, placebo-controlled trial. 151 patients were randomly assigned to either six weeks titration and ten weeks high-dose baclofen (N=58; up to 150mg), low-dose baclofen (N=31; 30mg), or placebo (N=62). The primary outcome measure was time to first relapse. Nine of the 58 patients (15.5%) in the high-dose group reached 150mg and the mean baclofen dose in this group was 93.6mg (SD=40.3). No differences between the survival distributions for the three groups were found in the time to first relapse during the ten-weeks high-dose phase (χ2=0.41; p=0.813) or the 16-weeks complete medication period (χ2=0.04; p=0.982). There were frequent dose-related adverse events in terms of fatigue, sleepiness, and dry mouth. One medication related serious adverse event occurred in the high-dose baclofen group. Neither low nor high doses of baclofen were effective in the treatment of AD. Adverse events were frequent, although generally mild and transient. Therefore, large-scale prescription of baclofen for the treatment of AD seems premature and should be reconsidered.

Which panic disorder patients benefit from which treatment: cognitive therapy or antidepressants?

BACKGROUND: Beliefs about the controllability of a disorder may be relevant in the causation, maintenance and treatment of disorders. We investigated whether congruence between patients' beliefs about controllability of a panic disorder and the type of treatment provided predicted outcome. METHODS: The differential effectiveness of cognitive therapy and antidepressant treatment (paroxetine or clomipramine) was investigated in a sample of 129 panic disorder patients in a 12-week, pretest posttest placebo-controlled study. Panic frequency, agoraphobic avoidance, anxiety, depression, and disability were measured with various validated interviewer and self-report measures. Beliefs about controllability were measured with the Multidimensional Anxiety Locus of Control Scale measuring an internal, chance, therapist and medication locus of control. In order to analyze aptitude-treatment interactions a new strategy called the Regression Trunk Approach was used in addition to classical hierarchical multiple regression analysis. RESULTS: Using the Regression Trunk Approach we found that locus of control orientation (LOC) predicted the differential effectiveness of cognitive therapy. Those patients with a medium internal LOC who received cognitive therapy performed significantly better than all patients who received a placebo pill on 8 of the 10 outcome variables. We did not find a differential LOC effect for antidepressant treatment. No evidence for aptitude-treatment interactions using hierarchical multiple regression analysis was found. CONCLUSIONS: Moderately strong beliefs about self-control of panic disorder congruent with the cognitive intervention provided seem to moderate treatment effectiveness. Future studies must be more attentive to the nonlinear effects of patient characteristics on the outcome of different types of treatments.

Stress-induced cortisol elevations are associated with impaired delayed, but not immediate recall.

Glucocorticoids are known to modulate memory functions, with elevated cortisol levels being associated with impaired declarative memory. This specific effect has been shown in several studies using pharmacological doses of cortisol. The present study was designed to assess the effects of stress-induced cortisol elevations on (1) the type of memory processing (encoding, consolidation and retrieval), and (2) on the emotional valence of the material under study. Sixteen healthy females were presented neutral and emotional material (words and paragraphs) before and after a stress challenge. Declarative memory was tested immediately after presentation and 24 h later (delayed recall). Delayed, but not immediate recall of the information presented after the stress challenge was significantly reduced compared with delayed recall of information presented before the stress challenge. In line with this, strong negative correlations were found for delayed recall of words and spatial memory presented after the challenge with post-stress cortisol levels, whereas no significant correlations were found between cortisol levels and delayed recall at day 1. These results suggest that stress-induced cortisol specifically affects long-term consolidation of declarative memories. These findings may have implications for understanding the effects of traumatic stress on memory functioning in patients with stress-related psychiatric disorders.

Evidence-based pharmacotherapy of panic disorder.

This paper reviews the literature on the pharmacotherapy of panic disorder, in order to address the questions (1) what is the first-line pharmacotherapy of choice for panic disorder?, (2) for how long should maintenance pharmacotherapy be continued, and (3) what is the optimal approach to the treatment-refractory patient with panic disorder. A MEDLINE search (1966-2003) was undertaken to collate randomized controlled trials of pharmacotherapy in panic disorder. A review of the evidence indicates that SSRIs are currently the first line agent of choice in panic disorder, and that pharmacotherapy should be continued for at least 1 year. There has been relatively little research on the pharmacotherapy of treatment-refractory panic disorder, and this area requires future attention.

A cluster randomized trial comparing two interventions to improve treatment of major depression in primary care.

BACKGROUND: Many patients with major depression are non-adherent to antidepressant medication and do not receive care according to current guidelines. There is increasing evidence that treatment of depression in primary care can be improved. Comparison between effective interventions may help to establish the active ingredients of such interventions. METHOD: In a randomized trial two interventions to improve treatment of major depression in primary care were compared (1) a depression care programme, targeting general practitioners (GPs), patients, and systematic follow-up, and (2) a systematic follow-up programme. Thirty GPs were randomized and 211 primary-care patients with current major depression were included. All patients were prescribed a selective serotonin reuptake inhibitor. Outcome measures included adherence to antidepressant medication, and depression outcome. RESULTS: No significant differences in adherence rates and treatment outcome measures were demonstrated between interventions at week 10 or week 26. Adherence rates were high and treatment outcome was favourable. CONCLUSIONS: The depression care programme was not superior to the systematic follow-up programme. Systematic follow-up in depression treatment in primary care seems to be an intervention per se, having the potential to improve adherence and treatment outcome.

Improving adherence to antidepressants: a systematic review of interventions.

BACKGROUND: Effectiveness of antidepressant medication is reduced by patients' nonadherence. Several interventions to improve adherence in patients diagnosed with unipolar depression have been tested. OBJECTIVE: To systematically review the effectiveness of interventions that aimed to improve adherence to antidepressant medication in patients with unipolar depression. METHOD: Systematic review of English-language articles of randomized controlled trials obtained by a computerized literature search of MEDLINE (1966-January 2002) using the terms patient compliance, patient dropout, treatment refusal, patient education, adherence, clinical trial, randomized controlled trial, controlled trial, depressive disorder, and depression; PSYCINFO (1984-January 2002) using the terms random, clinical, control, trial, adherence, compliance, noncompliance, dropouts, patient education, depression, major depression, affective disorders, and dysthymic disorder; EMBASE (1980-January 2002) using the terms patient compliance, patient dropouts, illness behavior, treatment refusal, patient education, clinical trial, controlled study, randomized controlled trial, and depression; and the Cochrane Controlled Trials Register (no restrictions) using the terms random*, complian*, adheren*, pharmacotherapy, regimen*, educat*, medicat*, depression, and depressive disorder. RESULTS: Educational interventions to enhance adherence failed to demonstrate a clear benefit on adherence and depression outcome. However, collaborative care interventions tested in primary care demonstrated significant improvements in adherence during the acute and continuation phase of treatment and were associated with clinical benefit, especially in patients suffering from major depression who were prescribed adequate dosages of antidepressant medication. CONCLUSION: We found evidence to support the introduction of interventions to enhance adherence with antidepressant medication in primary care, not only because of better adherence but also because of better treatment results. Because collaborative care interventions require additional resources, a better understanding of the mode of action of different programs is needed to reduce avoidable costs. The effectiveness of educational interventions needs more evidence.

The relevance of psychiatric and somatic comorbidity in depressed chronic benzodiazepine users.

BACKGROUND: Comorbid conditions may add to the burden of depressed patients and hamper their treatment. We therefore investigated the impact of anxiety disorders and somatic comorbidity in a group of depressed chronic benzodiazepine users on disease status, treatment, benzodiazepine history and discontinuation outcome. METHODS: At screening for a discontinuation programme, full psychiatric status was determined using the MINI-interview and psychopathology was assessed using several rating scales. Relevant medical history, including surgeries, was recorded as well. RESULTS: Patients with comorbid anxiety disorders were 8 years younger (p < 0.001), more anxious (p = 0.004) and reported more benzodiazepine withdrawal symptoms (p = 0.011) than depressed patients without comorbid anxiety disorders. They also had been using more long-acting benzodiazepines (p = 0.003), in higher dosages (p = 0.019). However, this did not result in more difficulty in tapering off benzodiazepines, either at post-test, or at follow-up 2.3 years later. Somatic comorbidity was not associated with the level of psychopathology and not related to the outcome of the discontinuation programme. CONCLUSIONS: Comorbid anxiety disorders are associated with a more severe disease status in depressed chronic benzodiazepine users, but have no influence on the benzodiazepine discontinuation. Somatic comorbidity has no impact on the severity of the psychopathology, or on benzodiazepine discontinuation.

Relevance of assessment of cognitions during panic attacks in the treatment of panic disorder.

BACKGROUND: In this paper the effects of cognitive therapy on the belief in causal catastrophic misinterpretations (CCMs) of bodily sensations in panic disorder patients were studied. METHODS: CCMs were formulated at the start of treatment and assessed at every treatment session for credibility during panic attacks and during that session. The relation between the belief in CCMs and other measures of panic was also studied. Sixty-six patients rated their belief in 1-3 CCMs during treatment with cognitive therapy. They also filled in questionnaires (ACQ and BSQ) at the start and end of treatment and kept a panic diary. RESULTS: The belief in CCMs diminished significantly in the course of treatment. A significant correlation between panic frequency and belief in CCMs during panic attacks, but not during treatment sessions, was found. Relations between improvement in panic frequency, ACQ- and BSQ-scores on the one hand and belief in CCMs on the other, also revealed significant correlations with belief ratings during panic attacks only. CONCLUSIONS: Especially ratings of belief during panic attacks are important in assessing the outcome of cognitive therapy in panic disorder. This measure can be considered as a severity measure. Belief in CCMs during treatment sessions seems to have little clinical significance.

Locus of control orientation in panic disorder and the differential effects of treatment.

BACKGROUND: In this study the effects of treatment with cognitive therapy, antidepressants or pill-placebo on the locus of control orientation in panic disorder patients were analysed, as well as the relation of this panic locus of control with panic frequency and cognitive measures of panic. METHODS: A Multidimensional Anxiety Locus of Control scale (MALC) was developed and completed with other measures (ACQ and BSQ) before and after treatment. Patients also kept a panic diary. RESULTS: Four subscales were derived from the MALC: one Internal, and three external (a Chance, a Medication, and a Therapist) locus of anxiety control orientation scales. Cognitive therapy was superior over pill-placebo on most outcome measures whereas antidepressants were only superior in reducing the number of panic attacks. Treatment with cognitive therapy resulted in an increase of 'internal' anxiety control orientation and a decrease of 'chance' and 'medication' orientation, in comparison with antidepressant therapy. The residualized gain scores on the MALC subscales correlated with clinical improvement in subjects treated with cognitive therapy only. CONCLUSIONS: Results suggest that the locus of control orientation is important in evaluating the differential effects of treatments in panic disorder. A differential effect on panic locus of control in favor of cognitive therapy in comparison to medication was found.