Long-term safety and cognitive effects of galantamine in the treatment of probable vascular dementia or Alzheimer's disease with cerebrovascular disease.

The relationship between cholinergic dysfunction and cognitive and functional impairment in patients with vascular dementia (VaD) and Alzheimer's disease (AD) with cerebrovascular disease (CVD) suggests a potential role for cholinomimetic therapy. Initial studies of galantamine demonstrated cognitive, behavioral, and functional benefits in these populations. 326 patients with VaD or AD with CVD who completed an initial 12-month trial were treated with galantamine 24 mg/day in a 24-month, open-label extension. This interim analysis was performed at month 12 of the open-label extension (248 completed the trial). Galantamine (up to 24 months total) was well tolerated in both groups. The most frequently reported adverse events, characteristic of older dementia patients, included depression, agitation, and insomnia. Gastrointestinal adverse events were less common than initially, indicating declining incidence with long-term therapy. Patients taking galantamine for the entire study demonstrated the least cognitive decline on AD Assessment Scale-cog/11: 2.7 points vs. 3.1 points in those given placebo initially (P < 0.001 and P = 0.003, respectively). The long-term benefits of galantamine were evident in both groups; cognitive baseline levels were maintained for approximately 21 months in VaD patients and for 12 months in patients with AD with CVD. Long-term (up to 24 months) galantamine therapy in patients with VaD and AD with CVD is well tolerated and associated with prolonged maintenance of cognitive function.

Anxiety sensitivity: relations to psychopathy, DSM-IV personality disorder features, and personality traits.

Relatively few data are available concerning the relations between anxiety sensitivity (AS) and both abnormal and normal personality traits. In particular, little is known about the associations between AS and personality disorders, although Shostak and Peterson [Behav. Res. Ther. 28 (1990) 513.] hypothesized that AS would be negatively correlated with antisocial personality disorder (ASPD) and perhaps related conditions (e.g., psychopathy). We examined the relations between AS, as assessed by the AS Index (ASI), and measures of psychopathy/ASPD, personality disorder features. and personality traits in a sample of 104 undergraduates. The ASI was not significantly associated with global measures of psychopathy or ASPD, although it was negatively correlated in some cases with the core affective deficits of psychopathy. In addition, the ASI was positively correlated with features of several Clusters B (e.g., borderline) and C (e.g., dependent) personality disorders and with features of passive-aggressive personality disorder. In addition, the ASI was positively associated with measures of several normal-range personality traits, including trait anxiety, alienation, well being, Negative Emotionality, and Constraint. Some, although not all, of the abnormal and normal personality correlates of the ASI were attributable to the variance shared by the ASI with trait anxiety measures. Implications and limitations of the present findings for the correlates and etiology of AS are outlined.

Coming to grips with negative evidence for the Comprehensive System for the Rorschach: a comment on Gacono, Loving, and Bodholdt; Ganellen; and Bornstein.

The Comprehensive System (CS; Exner, 1991, 1993) for the Rorschach is currently engulfed in controversy. This comment article responds to 3 articles by Rorschach proponents in this issue of the Journal of Personality Assessment. Contrary to the claims of Gacono, Loving, and Bodholdt (this issue), CS scores do not bear a well-demonstrated relationship to psychopathy, antisocial personality disorder, or conduct disorder. Contrary to the claims of Ganellen (this issue), both the original and the revised CS Depression Index (Exner, 1993) bear little or no relationship to depression diagnoses. Furthermore, the scoring reliability of some CS scores is problematic. Although we agree with Bornstein (this issue) that Rorschach scores generally bear little or no relation to psychiatric diagnoses or self-report questionnaires, we believe this lack of relationship tends to disconfirm hypotheses concerning the validity of the Rorschach. In the spirit of the philosopher Sir Karl Popper, the Rorschach community should not minimize negative evidence or engage in post hoc arguments to immunize the CS against falsification.

APOE genotype: no influence on galantamine treatment efficacy nor on rate of decline in Alzheimer's disease.

Apolipoprotein E (APOE) has been extensively demonstrated to be a genetic risk factor for Alzheimer's disease (AD). Associations of APOE genotype have been reported with age at AD onset, rate of decline, and responsiveness to therapy. This study aimed to test these hypotheses in a large study population of AD patients. APOE genotype was determined from 1,528 Caucasian subjects, diagnosed by NINCDS/ADRDA criteria as probable AD patients, enrolled in four international placebo-controlled clinical trials of 3--12 months duration, designed to evaluate efficacy of treatment with galantamine or sabeluzole. In addition to patient demographics and baseline scores for Mini Mental State Examination, scores on the Disability Assessment for Dementia (DAD) and the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) were recorded at the start, during, and at the end of the study. APOE epsilon 4 homozygotes had a significantly lower age at disease onset compared to patients with other APOE genotypes. The epsilon 4 allele was significantly over-represented in females compared to males, and in the group of subjects with an AD family history. Based on longitudinal data of 504 placebo-treated AD patients, the linear annual rate of change in score was 5 points on the ADAS-cog scale and 11 on the DAD scale. The epsilon 4 allele copy number did not influence these rates of decline. Sabeluzole treatment was not effective in the overall group compared to the placebo-treated group, nor in any subgroup stratified by epsilon 4 allele count. Galantamine produced cognitive and functional improvement that were not affected by epsilon 4 allele count. In conclusion, our data confirm a strong association between epsilon 4 homozygotes and age at onset of AD but do not support an effect of epsilon 4 allele copy number on rate of cognitive and functional decline nor on the efficacy of galantamine in patients with AD.

Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group.

OBJECTIVE: To evaluate the efficacy and safety of galantamine in the treatment of Alzheimer's disease. DESIGN: Randomised, double blind, parallel group, placebo controlled trial. SETTING: 86 outpatient clinics in Europe and Canada. PARTICIPANTS: 653 patients with mild to moderate Alzheimer's disease. INTERVENTION: Patients randomly assigned to galantamine had their daily dose escalated over three to four weeks to maintenance doses of 24 or 32 mg. MAIN OUTCOME MEASURES: Scores on the 11 item cognitive subscale of the Alzheimer's disease assessment scale, the clinician's interview based impression of change plus caregiver input, and the disability assessment for dementia scale. The effect of apolipoprotein E4 genotype on reponse to treatment was also assessed. RESULTS: At six months, patients who received galantamine had a significantly better outcome on the 11 item cognitive subscale of the Alzheimer's disease assessment scale than patients in the placebo group (mean treatment effect 2.9 points for lower dose and 3.1 for higher dose, intention to treat analysis, P<0.001 for both doses). Galantamine was more effective than placebo on the clinician's interview based impression of change plus caregiver input (P<0.05 for both doses v placebo). At six months, patients in the higher dose galantamine group had significantly better scores on the disability assessment for dementia scale than patients in the placebo group (mean treatment effect 3.4 points, P<0.05). Apolipoprotein E genotype had no effect on the efficacy of galantamine. 80% (525) of patients completed the study. CONCLUSION: Galantamine is effective and well tolerated in Alzheimer's disease. As galantamine slowed the decline of functional ability as well as cognition, its effects are likely to be clinically relevant.

Science and pseudoscience in the development of eye movement desensitization and reprocessing: implications for clinical psychology.

The enormous popularity recently achieved by Eye Movement Desensitization and Reprocessing (EMDR) as a treatment for anxiety disorders appears to have greatly outstripped the evidence for its efficacy from controlled research studies. The disparity raises disturbing questions concerning EMDR's aggressive commercial promotion and its rapid acceptance among practitioners. In this article, we: (1) summarize the evidence concerning EMDR's efficacy; (2) describe the dissemination and promotion of EMDR; (3) delineate the features of pseudoscience and explicate their relevance to EMDR; (4) describe the pseudoscientific marketing practices used to promote EMDR; (5) analyze factors contributing to the acceptance of EMDR by professional psychologists; and (6) discuss practical considerations for professional psychologists regarding the adoption of EMDR into professional practice. We argue that EMDR provides an excellent vehicle for illustrating the differences between scientific and pseudoscientific therapeutic techniques. Such distinctions are of critical importance for clinical psychologists who intend to base their practice on the best available research.

Galantamine: additional benefits to patients with Alzheimer's disease.

Galantamine, a novel treatment for Alzheimer's disease (AD), has a dual mechanism of action, combining allosteric modulation of nicotinic acetylcholine receptors with reversible, competitive inhibition of acetylcholinesterase. In the Phase III clinical trial programme, over 3,000 patients with mild-to-moderate AD were enrolled in one of five randomized, controlled, double-blind studies. Using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) to assess memory and other cognitive functions, galantamine was found to be significantly superior to placebo in all five studies at doses of 16, 24 and 32 mg/day. In all studies, galantamine-treated patients maintained their cognitive function, whereas the placebo-treated patients experienced a significant deterioration in ADAS-cog scores. The 32-mg/day dose was not associated with any additional cognitive benefit. Pooled data from two 6-month studies (n = 1,269), which were of identical design, show that the therapeutic benefits of galantamine are sustained for the duration of treatment. The treatment effect (galantamine-placebo difference on ADAS-cog) for the pooled data was approximately 4 points. Clinical benefit was seen in all levels of disease severity, with a 7-point advantage over placebo on ADAS-cog for patients with moderately severe disease. Galantamine was well tolerated, with most patients completing the 6-month studies. The long-term effects of galantamine have been evaluated in a 12-month study. Patients who completed one of the pivotal 6-month studies (n = 353) were entered into a 6-month open-label extension. Cognitive and daily function were maintained throughout the 12 months in patients who received galantamine 24 mg/day. This sustained level of benefit may reflect galantamine's dual effect on the cholinergic system. Data from a 5-month, placebo-controlled study have also shown that galantamine produces significant benefits on behavioural symptoms. The persistence and range of therapeutic effects produced by galantamine suggest that it may provide additional benefits for patients with AD.

Construct validity of the Psychopathic Personality Inventory in a correctional sample.

The relations between the Psychopathic Personality Inventory (PPI; Lilienfeld & Andrews, 1996) and 4 theoretically related constructs (empathy, aggression, work ethic, and borderline personality disorder) were examined. Additionally, the relation between the PPI and heroism was explored. One hundred male inmates were administered the PPI, the Questionnaire Measure of Emotional Empathy (Mehrabian & Epstein, 1972), the Aggression Questionnaire (Buss & Perry, 1992), the Protestant Ethic Scale (Mirels & Garrett, 1971), the Self-Report for Borderline Personality Scale (Oldham et al., 1985), and the Activity Frequency Inventory (Lilienfeld, 1998). As predicted, the PPI was significantly negatively correlated with empathy and significantly positively related to aggression and borderline personality. Contrary to prediction, the correlation between the PPI and work ethic was not significant. Eight of 11 hypotheses regarding the relations of the PPI subscales to these 4 constructs were corroborated. Results support the construct validity of the PPI in a correctional sample. The exploratory analysis of the relation between the PPI and heroism revealed no significant relations.

A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group.

OBJECTIVE: To investigate the efficacy and tolerability of galantamine, using a slow dose escalation schedule of up to 8 weeks, in 978 patients with mild to moderate AD. METHODS: A 5-month multicenter, placebo-controlled, double-blind trial. Following a 4-week placebo run-in, patients were randomized to one of four treatment arms: placebo or galantamine escalated to final maintenance doses of 8, 16, or 24 mg/day. Outcome measures included the cognitive subscale of the AD Assessment Scale (ADAS-cog), the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus), the AD Cooperative Study Activities of Daily Living inventory, and the Neuropsychiatric Inventory. Standard safety evaluations and adverse event monitoring were carried out. RESULTS: After 5 months, the galantamine-placebo differences on ADAS-cog were 3.3 points for the 16 mg/day group and 3.6 points for the 24 mg/day group (p < 0.001 versus placebo, both doses). Compared with placebo, the galantamine 16- and 24-mg/day groups also had a significantly better outcome on CIBIC-plus, activities of daily living, and behavioral symptoms. Treatment discontinuations due to adverse events were low in all galantamine groups (6 to 10%) and comparable with the discontinuation rate in the placebo group (7%). The incidence of adverse events in the galantamine groups, notably gastrointestinal symptoms, was low and most adverse events were mild. CONCLUSIONS: Galantamine 16 and 24 mg/day significantly benefits the cognitive, functional, and behavioral symptoms of AD as compared with placebo. Slow dose escalation appears to enhance the tolerability of galantamine, minimizing the incidence and severity of adverse events.

The Rorschach test in clinical diagnosis: a critical review, with a backward look at Garfield (1947).

The present article comments on a classic study by Garfield (1947) then reviews research on the Rorschach and psychiatric diagnoses. Despite a few positive findings, the Rorschach has demonstrated little validity as a diagnostic tool. Deviant verbalizations and bad form on the Rorschach, and indices based on these variables, are related to Schizophrenia and perhaps to Bipolar Disorder and Schizotypal Personality Disorder. Patients with Borderline Personality Disorder also seem to give an above-average number of deviant verbalizations. Otherwise the Rorschach has not shown a well-demonstrated relationship to these disorders or to Major Depressive Disorder, Posttraumatic Stress Disorder (PTSD), anxiety disorders other than PTSD, Dissociative Identity Disorder, Dependent, Narcissistic, or Antisocial Personality Disorders, Conduct Disorder, or psychopathy.

A meta-analytic review of the relation between antisocial behavior and neuropsychological measures of executive function.

Previous narrative reviews of the relation between antisocial behavior (ASB) and neuropsychological tests of executive functioning (EF) have raised numerous methodological concerns and produced equivocal conclusions. By using meta-analytic procedures, this study attempts to remedy many of these concerns and quantifies the relation between ASB and performance on six reasonably well validated measures of EF. Thirty-nine studies yielding a total of 4,589 participants were included in the analysis. Overall, antisocial groups performed .62 standard deviations worse on EF tests than comparison groups; this effect size is in the medium to large range. Significant variation within this effect size estimate was found, some of which was accounted for by differences in the operationalizations of ASB (e.g., psychopathy vs. criminality) and measures of EF. Evidence for the specificity of EF deficits relative to deficits on other neuropsychological tasks was inconsistent. Unresolved conceptual problems regarding the association between ASB and EF tests, including the problem of localizing EF tests to specific brain regions, are discussed.

The Scientific Status of Projective Techniques.

Although projective techniques continue to be widely used in clinical and forensic settings, their scientific status remains highly controversial. In this monograph, we review the current state of the literature concerning the psychometric properties (norms, reliability, validity, incremental validity, treatment utility) of three major projective instruments: Rorschach Inkblot Test, Thematic Apperception Test (TAT), and human figure drawings. We conclude that there is empirical support for the validity of a small number of indexes derived from the Rorschach and TAT. However, the substantial majority of Rorschach and TAT indexes are not empirically supported. The validity evidence for human figure drawings is even more limited. With a few exceptions, projective indexes have not consistently demonstrated incremental validity above and beyond other psychometric data. In addition, we summarize the results of a new meta-analysis intended to examine the capacity of these three instruments to detect child sexual abuse. Although some projective instruments were better than chance at detecting child sexual abuse, there were virtually no replicated findings across independent investigative teams. This meta-analysis also provides the first clear evidence of substantial file drawer effects in the projectives literature, as the effect sizes from published studies markedly exceeded those from unpublished studies. We conclude with recommendations regarding the (a) construction of projective techniques with adequate validity, (b) forensic and clinical use of projective techniques, and (c) education and training of future psychologists regarding projective techniques.

The Rorschach Inkblot Test: a case of overstatement?

In the 1940s, inflated claims were often made regarding the Rorschach Inkblot Test. Over half a century later, overstatements regarding the test are still common. The present article identifies problems with the Rorschach regarding norms, cultural sensitivity, interrater reliability, test-retest reliability, validity, factor structure, and accessibility of supporting studies. Contrary to overstated claims made on behalf of the Rorschach, the test continues to be a highly problematic instrument from a psychometric standpoint.

The association between anxiety and psychopathy dimensions in children.

Although several theoretical models posit that low levels of anxiety are a risk factor for psychopathy and antisocial behavior, a number of studies have reported elevated levels of anxiety among antisocial individuals. Nevertheless, most investigators in this literature have not distinguished between fearfulness and trait anxiety or attempted to separate the antisocial lifestyle dimension from the callous and unemotional dimension of psychopathy. In a study of clinically referred children (N = 143), we found that (a) measures of trait anxiety and fearlessness (low fearfulness) exhibited low correlations; (b) conduct problems tended to be positively correlated with trait anxiety, whereas callous and unemotional traits tended to be negatively correlated with trait anxiety; and (c) controlling statistically for the effects of one dimension increased the divergent correlations of the other dimension with both trait anxiety and fearful inhibition. These findings bear potentially important implications for the diagnosis and etiology of psychopathy and antisocial behavior and suggest that distinctions between trait anxiety and fearful inhibition, as well as between the two dimensions of psychopathy, may help to clarify longstanding confusion in this literature.

A preliminary investigation of the construct of psychopathic personality (psychopathy) in chimpanzees (Pan troglodytes).

Although the construct of psychopathy has received considerable attention in humans, its relevance to other animals is largely unknown. We developed a measure of psychopathy for use in chimpanzees (Pan troglodytes), the Chimpanzee Psychopathy Measure (CPM), and asked 6 raters to complete this index on 34 chimpanzees. The CPM (a) demonstrated satisfactory interrater reliability and internal consistency; (b) exhibited marginally significant sex differences (males > females); (c) correlated positively with measures of extraversion, agreeableness, and observational ratings of agonism, sexual activity, daring behaviors, teasing, silent bluff displays, and temper tantrums, and negatively with observational ratings of generosity; and (d) demonstrated incremental validity above and beyond a measure of dominance. Although further validation of the CPM is needed, these findings suggest that the psychopathy construct may be relevant to chimpanzees.