Drug Effects: Do Test Results Correlate With Clinical Gains?

March 3, 2007

There are any number of ways to measure the effects of psychoactive medications, ranging from objective assessments of behavioral change to neuropsychological testing to subjective global ratings by physicians or patients. Several recent studies have examined the question of whether medication-induced improvements in neuropsychological test performance correlated with gains in healthful functioning.

There are any number of ways to measure the effects of psychoactive medications, ranging from objective assessments of behavioral change to neuropsychological testing to subjective global ratings by physicians or patients. Several recent studies have examined the question of whether medication-induced improvements in neuropsychological test performance correlated with gains in healthful functioning.

Social competence and social cognition were suggested as viable outcome measures for clinical trials by one research group.1 Improved executive functioning, one neuropsychological measure of capacity for social and occupational functioning, was correlated with therapeutic drug effect in another study.2 A third group of researchers sought a link between medication treatment efficacy and such complex states as consideration of others, personal responsibility, and self-esteem.3

In an 8-week clinical trial comparing the efficacy and tolerability of quetiapine (Seroquel) and risperidone (Risperdal), Harvey and colleagues1 ascertained changes in social competence, rated with the Social Skills Performance Assessment, a validated measure of interactive social skills, along with changes in social cognition, assessed with the Penn Emotional Acuity Test, which indexes the ability to perceive intensity of affective expression.

The researchers indicated that this was the first study of antipsychotic effects that used performance-based measures of social competency. They credited the impetus for the study to an FDA-NIMH workshop on trial design that recommended the use of performance-based measures of functional capacity in clinical trials involving patients with schizophrenia.4

“While neuropsychological test performance is correlated with social outcomes in patients with schizophrenia,” Harvey and colleagues explained, “there is little evidence to date that changes in neuropsychological performance are associated with changes in these outcomes.”

The researchers found little difference between the 2 antipsychotic treatments on the improvement of symptoms, measured with the PANSS (Positive and Negative Syndrome Scale), but a reduction in PANSS total score with quetiapine treatment predicted improvement in delayed recall, and an improved PANSS measure of positive symptoms predicted improvements in total learning. Risperidone-associated changes in positive symptoms were related to improvements in Rey Auditory Verbal Learning Test performance and in total learning.

“Social competence measures are positively affected by treatment with atypical antipsychotics,” the research-ers concluded. “These treatment-related changes in social skills performance are correlated with concurrent improvement in neuropsychological performance.”

The researchers noted that 20% of the variance in improvements in neuropsychological performance and social competence overlapped, and so suggested that the benefit of the medications on cognitive performance is also related to these changes in functional skills. Since most previous studies of atypical antipsychotics and cognition had not incorporated assessments of functional outcomes, the authors noted, it could only be assumed that cognitive changes had functional relevance.

Improvements in executive function versus positive symptoms
In a separate study with olanzapine (Zyprexa) and clozapine (Clozaril), researchers in Germany sought to determine whether changes in executive function are independent of medication treatment–related changes in the positive symptoms of schizophrenia, measured on the PANSS, or improvement in extrapyramidal drug adverse effects (EPS), assessed using the Simpson-Angus Scale. The study was designed to distinguish between the drugs in their effect on executive function, which was measured with the Stroop Test, the Tower of London Test, and the Short Wisconsin Card Sorting Test.

The investigators found these agents comparable in improving both psychopathology and executive function and also found that improvements in executive function were independent of reduction in positive symptoms or EPS. “We therefore consider the improvement of executive functioning to be a primary effect of the treatment with olanzapine and clozapine,” the researchers reported, “not mediated by changes in positive symptoms and adverse . . . events.” 1

Divalproex and self-esteem
A 7-week evaluation of divalproex (Depakote) in conduct disorder in youth assessed “emotional cognitions” using the Weinberger Adjustment Inventory. The researchers characterized these emotional cognitive states as basic, including anger, depression, happiness, and anxiety; and more complex, including the consideration of others, personal responsibility, and self-esteem. Khanzode and coauthors 3 describe theirs as a “rare clinical trial” to provide evidence of different levels of efficacy of medication treatment.

“We dissected the effects of this particular compound on the different levels of psychological functioning-emotions and other socio-emotional cognitions,” they indicated. They reported an improvement in depression symptoms with high-dose divalproex, but no apparent medication effect on anxiety, anger, or happiness. In the more complex states, impulse control was improved but the investigators reported only “marginal improvement” in self- confidence and personal responsibility.

“This study clearly helps us understand the different levels of efficacy of a medication like divalproex, which affects the simpler/basic emotions first and does not go to more complex states . . . thus pointing toward the need of other measures of intervention like psychotherapy to affect the highly complex level of psychological functioning,” the investigators concluded.

References:

References1. Harvey PD, Patterson TL, Potter LS, et al. Improvement in social competence with short-term atypical antipsychotic treatment: a randomized, double-blind comparison of quetiapine versus risperidone for social competence, social cognition, and neuropsychological functioning. Am J Psychiatry. 2006;163:1918-1925.
2. Bender S, Dittmann-Balcar A, Schall U, et al. Influence of atypical neuroleptics on executive functioning in patients with schizophrenia: a randomized, double-blind comparison of olanzapine vs. clozapine. Int J Neuropsychopharm. 2005;9:135-145.
3. Khanzode LA, Saxena K, Kraemer H, et al. Efficacy profiles of psychopharmacology: divalproex sodium in conduct disorder. Child Psychiatry Hum Dev. 2006;37:55-64.
4. Buchanan RW, Davis M, Goff D, et al. A summary of the FDA-NIMH MATICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull. 2005;31:5-19.