Patterns of long-term and short-term responses in adult patients with attention-deficit/hyperactivity disorder in a completer cohort of 12 weeks or more with atomoxetine.

BACKGROUND: Atomoxetine is a well-established pharmacotherapy for adult ADHD. Long-term studies show incremental reductions in symptoms over time. However, clinical experience suggests that patients differ in their response patterns. METHODS: From 13 Eli Lilly-sponsored studies, we pooled and analyzed data for adults with ADHD who completed atomoxetine treatment at long-term (24 weeks; n=1443) and/or short-term (12 weeks; n=2830) time-points, and had CAARS-Inv:SV total and CGI-S data up to or after these time-points and at Week 0 (i.e. at baseline, when patients first received atomoxetine). The goal was to identify and describe distinct trajectories of response to atomoxetine using hierarchical clustering methods and linear mixed modelling. RESULTS: Based on the homogeneity of changes in CAARS-Inv:SV total scores, 5 response clusters were identified for patients who completed long-term (24 weeks) treatment with atomoxetine, and 4 clusters were identified for patients who completed short-term (12 weeks) treatment. Four of the 5 long-term clusters (comprising 95% of completer patients) showed positive trajectories: 2 faster responding clusters (L1 and L2), and 2 more gradually responding clusters (L3 and L4). Responses (i.e.≥30% reduction in CAARS-Inv:SV total score, and CGI-S score≤3) were observed at 8 and 24 weeks in 80% and 95% of completers in Cluster L1, versus 5% and 48% in Cluster L4. CONCLUSIONS: While many adults with ADHD responded relatively rapidly to atomoxetine, others responded more gradually without a clear plateau at 24 weeks. Longer-term treatment may be associated with greater numbers of responders.

The effects of atomoxetine on emotional control in adults with ADHD: An integrated analysis of multicenter studies.

PURPOSE: To investigate the effects of atomoxetine on emotional control in adults with ADHD. METHODS: We performed an integrated analysis using individual patient data pooled from three Eli Lilly-sponsored studies. An integrated analysis can be viewed as a meta-analysis of individual patient-level data, rather than study-level summary data. RESULTS: Two populations were identified: a large sample of patients with pre-treatment baseline data (the "overall population"; n=2846); and a subset of these patients with placebo-controlled efficacy data from baseline to 10 or 12 weeks after initiating treatment (the "placebo-controlled population"; n=829). At baseline, in the overall population, ∼50% of ADHD patients had BRIEF-AS (Behavior Rating Inventory of Executive Function-Adult Version Self-Report) Emotional control subscores between 21 and 30, compared with ∼10% of normative subjects in the BRIEF-A manual. At endpoint, in the placebo-controlled population, atomoxetine led to a small (effect size 0.19) but significant (P=0.013) treatment effect for emotional control. The effect size was 0.32 in patients with BRIEF-AS Emotional control scores>20 at baseline. Improvements in emotional control correlated with improvements in the core ADHD symptoms and quality-of-life. DISCUSSION: As deficient emotional control is associated with impaired social, educational and occupational functioning over and above that explained by core ADHD symptoms alone, improvements in emotional control may be clinically relevant. CONCLUSION: At baseline, adults with ADHD were more likely to have impaired emotional control than normative subjects. In the adult ADHD patients, atomoxetine treatment was associated with improvements in emotional control, as well as in core ADHD symptoms and quality-of-life.

Predictors of remission with placebo using an integrated study database from patients with major depressive disorder.

OBJECTIVE: To identify predictors of remission with placebo treatment in double-blind randomized controlled trials (RCTs) in major depressive disorder (MDD). METHOD: A total of 1017 placebo-treated patients with baseline Hamilton Depression rating scale (HAMD) total ≥15 from eight duloxetine RCTs were included. Remission was defined as endpoint (7-8 weeks) HAMD total ≤7. Data were randomly split into training data (N = 813, 80%) for model selection and test data (N = 204, 20%) for validation. Logistic regression and classification and regression tree (CART) methods were used to identify predictors of remission. Predictive accuracy of models was assessed by Receiver Operator Characteristic (ROC) curves. RESULTS: Baseline predictors for remission with placebo consistently identified with the logistic regression and CART analysis were less severe depressive symptoms (based on HAMD core symptoms), younger age, less anxiety (based on HAMD anxiety/somatization), and shorter current MDD episode duration. Associated cut-off values from the CART method characterized patient groups according to their remission likelihood. However, the predictive accuracy was modest for both methods with areas under the ROC curve of 0.6-0.65 based on test data. CONCLUSION: The derived models, although of limited value for predicting remission in individual patients, may be useful for adjusting for placebo effects in clinical trials.

In search of optimal lithium levels and olanzapine doses in the long-term treatment of bipolar I disorder. A post-hoc analysis of the maintenance study by Tohen et al. 2005.

PURPOSE: The aim of this study was to investigate whether lower lithium levels (LoLi) or olanzapine doses (LoOL) are risk factors for future mood episodes in patients with bipolar I disorder. METHODS: A post-hoc analysis of the olanzapine-lithium-maintenance study [31] was performed using proportional hazards Cox regression models and marginal structural models (MSMs), adjusting for non-random assignments of dose during treatment. RESULTS: The LoLi group (<0.6 mmol/L) had a significantly increased risk of manic/mixed (hazard ratio [HR]=1.96, p=0.042), but not depressive (HR=2.11, p=0.272) episodes, compared to the combined medium (0.6-0.79 mmol/L) and high lithium level (≥0.8 mmol/L) groups. There was no significant difference in risk between the two higher lithium level groups (0.6-0.79 mmol/L; ≥0.8 mmol/L) for new manic/mixed (HR=0.96, p=0.893) or depressive (HR=0.95, p=0.922) episodes. The LoOL group (<10mg/day) showed a significantly increased risk of depressive (HR=2.24, p=0.025) episodes compared to the higher olanzapine (HiOL) dose group (HiOL: 10-20 mg/day), while there was no statistically significant difference in risk for manic/mixed episodes between the two groups (HR=0.94, p=0.895). CONCLUSION: Lithium levels≥0.6 mmol/L and olanzapine doses≥10mg/day may be necessary for optimal protection against manic/mixed or depressive episodes, respectively in patients with bipolar I disorder.

Predictors of risk for relapse in patients with schizophrenia or schizoaffective disorder during olanzapine drug therapy.

PURPOSE: To evaluate the relationship of dose decrease, symptom worsening, and baseline covariates on subsequent relapse during olanzapine treatment in patients with schizophrenia or schizoaffective disorder. METHODS: In two 28-week, randomized, double-blind clinical trials, a Cox proportional hazards model was used to determine potential correlates of relapse (defined as > or =20% worsening on PANSS total and CGI-Severity 3) among patients (N=271) who responded to 8 weeks of olanzapine treatment (10-20mg/day). Variables examined included: demographics, illness characteristics, baseline symptoms, symptom change, dose, adverse events, and functioning. RESULTS: Patients with a lower last dose relative to the preceding visit interval were 4 times more likely to relapse during that visit interval than other patients (p<.001). A similar finding was observed for a decrease in interval modal dose, although this variable was more predictive of relapse in the visit interval immediately following dose decrease (p=.027). In a subgroup analysis by gender, there was a significantly greater incidence of relapse in men with a dose decrease, whereas a dose decrease in women did not correlate with relapse. Relapse was also correlated with the emergence or worsening of a psychiatric adverse event during the same (p<.001) and preceding (p=.007) visit intervals, and with increased rating scale measures of psychopathology. The occurrence of a non-psychiatric adverse event was not associated with relapse. CONCLUSION: Dose decrease is a significant predictor of relapse in male but not female patients. Psychiatric adverse events also predicted relapse. Patients should be periodically reassessed to determine the need for maintenance treatment with appropriate dose.

Effect of amantadine on weight gain during olanzapine treatment.

Patients treated with olanzapine may gain weight, especially in the first months of therapy. Amantadine (100-300 mg/day) was started in 12 patients having a mean weight gain of 7.3 kg during olanzapine treatment. The patients' weight stabilised and over 3-6 months they lost an average of 3.5 kg. No clinical deterioration occurred and no adverse effects were reported. These observations merit confirmation in randomised, controlled trials.

Inhibitory effect of piracetam on platelet-rich thrombus formation in an animal model.

Intravenous administration of piracetam to hamsters reduced the formation of a platelet-rich venous thrombus induced by a standardised crush injury, in a dose-dependent fashion with an IC50 of 68 +/- 8 mg/kg. 200 mg/kg piracetam also significantly reduced in vivo thrombus formation in rats. However, in vitro aggregation of rat platelets was only inhibited with piracetam-concentrations at least 10-fold higher than plasma concentrations (6.2 +/- 1.1 mM) obtained in the treated animals. No effects were seen on clotting tests. In vitro human platelet aggregation, induced by a variety of agonists, was inhibited by piracetam, with IC50's of 25-60 mM. The broad inhibition spectrum could be explained by the capacity of piracetam to prevent fibrinogen binding to activated human platelets. Ex vivo aggregations and bleeding times were only minimally affected after administration of 400 mg/kg piracetam i.v. to healthy male volunteers, resulting in peak plasma levels of 5.8 +/- 0.3 mM. A possible antiplatelet effect of piracetam could be due to the documented beneficial effect on red blood cell deformability leading to a putative reduction of ADP release by damaged erythrocytes. However similarly high concentrations were needed to prevent stirring-induced "spontaneous" platelet aggregation in human whole blood. It is concluded that the observed antithrombotic action of piracetam cannot satisfactorily be explained by an isolated direct effect on platelets. An additional influence of piracetam on the rheology of the circulating blood and/or on the vessel wall itself must therefore be taken into consideration.

Treatment of acute ischemic stroke with piracetam. Members of the Piracetam in Acute Stroke Study (PASS) Group.

BACKGROUND AND PURPOSE: Piracetam, a nootropic agent with neuroprotective properties, has been reported in pilot studies to increase compromised regional cerebral blood flow in patients with acute stroke and, given soon after onset, to improve clinical outcome. We performed a multicenter, randomized, double-blind trial to test whether piracetam conferred benefit when given within 12 hours of the onset of acute ischemic stroke to a large group of patients. METHODS: Patients received placebo or 12 g piracetam as an initial intravenous bolus, 12 g daily for 4 weeks and 4.8 g daily for 8 weeks. The primary end point was neurologic outcome after 4 weeks as assessed by the Orgogozo scale. Functional status at 12 weeks as measured by the Barthel Index was the major secondary outcome. CT scan was performed within 24 hours of the onset of stroke but not necessarily before treatment. Analyses based on the intention to treat were performed in all randomized patients (n = 927) and in an "early treatment" population specified in the protocol as treatment within 6 hours of the onset of stroke but subsequently redefined as less than 7 hours after onset (n = 452). RESULTS: In the total population, outcome was similar with both treatments (the mean Orgogozo scale after 4 weeks: piracetam 57.7, placebo 57.6; the mean Barthel Index after 12 weeks: piracetam 55.8, placebo 53.1). Mortality at 12 weeks was 23.9% (111/464) in the piracetam group and 19.2% (89/463) in the placebo group (relative risk 1.24, 95% confidence interval, 0.97 to 1.59; P = .15). Deaths were fewer in the piracetam group in those patients in the intention-to-treat population admitted with primary hemorrhagic stroke. Post hoc analyses in the early treatment subgroup showed differences favoring piracetam relative to placebo in mean Orgogozo scale scores after 4 weeks (piracetam 60.4, placebo 54.9; P = .07) and Barthel Index scores at 12 weeks (piracetam 58.6, placebo 49.4; P = .02). Additional analyses within this subgroup, confined to 360 patients with moderate and severe stroke (initial Orgogozo scale score < 55), showed significant improvement on piracetam in both outcomes (P < .02). CONCLUSIONS: Piracetam did not influence outcome when given within 12 hours of the onset of acute ischemic stroke. Post hoc analyses suggest that piracetam may confer benefit when given within 7 hours of onset, particularly in patients with stroke of moderate and severe degree. A randomized, placebo-controlled, multicenter study, the Piracetam Acute Stroke Study II (PASS II) will soon begin.

Piracetam as an adjuvant to language therapy for aphasia: a randomized double-blind placebo-controlled pilot study.

OBJECTIVE: To determine whether piracetam 4.8 g/day together with intensive language therapy improved language function more than language therapy alone. DESIGN: Double-blind, placebo-controlled parallel group study. SETTING: Referral speech and language clinic of a university department of neurology. PATIENTS: Sixty-six inpatients with aphasia present between 4 weeks and 36 months. INTERVENTIONS: Intensive language therapy for 6 weeks in all patients. Thirty-two patients received piracetam 4.8 g daily and 34 patients received placebo. MAIN OUTCOME MEASURE: The Aachen Aphasia Test (AAT), a standardized procedure for evaluating the severity of aphasia, was performed at baseline and after 6 weeks' treatment. RESULTS: In 50 patients evaluated for efficacy, a trend toward improvement in the active group was observed in all subtests of the AAT. This trend was statistically significant for absolute differences in recovery of "written language" and "profile level." CONCLUSION: Piracetam appears to have a positive adjuvant effect on the recovery of aphasia in patients receiving intensive language therapy.

Technetium-99m HMPAO SPET in acute supratentorial ischaemic infarction, expressing deficits as millilitre of zero perfusion.

A comparative interim analysis was performed of clinical parameters, computed tomographic (CT) scan results and technetium-99m hexamethylpropylene amine oxime single-photon emission tomography (SPET) findings obtained within 12 h of acute supratentorial ischaemic infarction. First, the applicability for SPET semiquantification in this study of the "method of Mountz", simultaneously accounting for extent and degrees of hypoperfusion by expressing deficits as millilitre of zero perfusion, was considered. Next, the relative contributions of perfusion SPET and CT scan in the acute stage of ischaemic infarction were compared in 27 patients (mean age 68.8 years). Finally, the correlation of SPET lesions with clinical parameters at onset was evaluated. The method of Mountz represents a workable, accurate virtual parameter, with the assumption that the contralateral brain region remains uninvolved. Interobserver reproducibility in 12 SPET studies, with lesions varying between 6 and 369 cc, showed a correlation coefficient r of 0.99. In practice, because of inconstant distribution of activities in the brain, the method can only be applied slice by slice and not on the total global volume. While the mean delay since the onset of symptomatology was approximately 7 h for both SPET and CT scan, SPET showed lesions concordant with the clinical neurological findings in 100% and CT scan in only 48%. One could hypothesize that SPET examinations performed later would show larger functional defects, because of the development of additional functional changes secondary to biochemical alterations. However, in this regard no statistically significant differences were found between two subproups, taking the median of delay before SPET examination as cut-off.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of piracetam on recovery and rehabilitation after stroke: a double-blind, placebo-controlled study.

The nootropic agent piracetam has been shown to improve learning and memory, and it may, by this means, facilitate recovery and rehabilitation after a stroke. We report the results of a pilot study exploring its effects in patients undergoing rehabilitation after acute cerebral infarction in the carotid artery territory. We compared piracetam and placebo, each given for 12 weeks, in a multicenter, double-blind, randomized trial of parallel-group design; testing was performed at baseline (6-9 weeks poststroke), weeks 5 and 12, and, in fewer patients, 12 weeks after termination of treatment. Standardized tests of activities of daily living (Barthel Index, Kuriansky Test), aphasia (Aachen Aphasia Test), and perception (Rivermead Perception Assessment Battery) were the primary efficacy variables. Of 158 patients, 137 (81 males, 56 females) were studied after treatment and 88 at 24-week follow-up. Thirty patients on piracetam (45%) and 37 on placebo (53%) were aphasic on entry. Both groups, including the subgroups with aphasia, were well matched at baseline for demographic data, stroke sequelae, type and severity of aphasia, and prognostic parameters. Multivariate analysis of Aachen Aphasia subtest scores showed a significant overall improvement relative to baseline in favor of piracetam (p = 0.02) at 12 weeks. This was not seen at 24 weeks when, however, fewer patients were available for evaluation so that we could neither confirm nor deny whether improvement was maintained after cessation of piracetam. We were unable to demonstrate an effect on tests of activities of daily living and could neither confirm nor exclude an effect on perceptual deficit. We have shown an improvement in aphasia in patients undergoing rehabilitation after a stroke after 12 weeks' treatment with piracetam that requires confirmation in further studies.

Interaction between psychological and pharmacological treatment in cognitive impairment.

In contrast to other kinds of psychotropic drugs, nootropics or cognition enhancing drugs may be indicated, not for the direct treatment of the pathology itself, but for improving or restoring the remaining brain functions. Brain functions are normally trained during various kinds of non-medical therapy, such as physiotherapy, speech therapy, occupational therapy, memory training etc... In research little attention has been paid to the combination of both kinds of therapeutic approaches, probably because of the important methodological difficulties. This combination however, offers various interesting perspectives: L. ISRAEL examined in two placebo-controlled studies the effects of either 160 mg/d of ginkgo biloba extractum (GBE) or piracetam 2.4 or 4.8 g/d, combined with a memory training program, in nondemented patients complaining of memory problems. The results of both studies suggest that nootropic drug treatment and memory training have each an effect on different cognitive functions and, hence, are complementary. Some functions, like attention/perception in the GBE study and learning in the piracetam study, seem to benefit from both treatments, suggesting a mutually potentiating effect of drug treatment and training. This potentiation is very clear in the treatment of dyslexic children: in a placebo-controlled study piracetam 3.3 g/d, in combination with normal school teaching and more specific logopedic therapy, allowed a normal progression during the full school year in reading accuracy and reading comprehension, while the placebo treated children getting a similar training progressed only with 50%. Recently promising results were obtained in the treatment of dysphasic patients with a combination of speech therapy and piracetam 4.8 g/d, especially when given during the first months after the stroke, or otherwise in combination with an intensive speech training. In both double-blind studies the piracetam treated group improved about 60% more than the group who only got speech therapy and placebo. All these data may be explained by the restorative or enhancing influence of nootropic drugs on neurotransmitter systems closely related to learning and memory functions. E.g. piracetam restores the availability and function of muscarinic and NMDA receptors in aging animals, most probably through a modulation of the psychico-chemical properties of the neuronal membrane such as the membrane fluidity.

[Effects of hydroxyzine on attention and memory in elderly subjects]. / Effets de l'hydroxyzine sur l'attention et la mémoire chez le sujet âgé.

A single intake of hydroxyzine 25 mg was compared to placebo, and lorazepam 1 mg as a verum, in a double-blind, triple-crossover trial. Each of the 12 elderly volunteers was tested on three different days, once under each condition. At 2.5 hours after drug intake they were assessed or reassessed for attention, immediate and delayed (30') memory, cognitive ability and feelings of anxiety and fatigue. Some subjects mentioned a minimal sedation under hydroxyzine 25 mg and under lorazepam 1 mg, but only hydroxyzine preserved memory and attention, while lorazepam caused clear deficiencies in memory recall.