Lundbeck_subbed.qxp 6/8/09 10:03 Page 28
Schizophrenia
Figure 4: Change in Neurocognitive Domains After SD, the cut-off measure of performance considered by most
Two Months of Antipsychotic Therapy
neuropsychologists to be within the normal range (see Figure 5). The
magnitude of these observed improvements is such that the idea of
0.7
simple practice effects, as demonstrated in CATIE, can be conclusively
0.6
rejected. Rather than a mild improvement of about 0.2 SD, these
0.5
patients were experiencing improvements in cognitive scores of a full
0.4
SD or more. The disparity in study data suggests a differential sampling
0.3
of patients: patients were eligible for the extension study only if they
0.2
were clinically responsive to drug therapy in the first six weeks of the
0.1 initial study, so these were not only patients who were treatment-
0 responsive, but were also patients who were treatment-adherent –
-0.1
characteristics that were absent in patients enrolled in the CATIE
Processing Reasoning Working Verbal Vigilance
speed memory memory
study. Moreover, patients in the extension study were maintained on
Change in Z-score from baseline to 2 months
the same medication for six months, whereas the average patient in
Olanzapine Perphenazine Quetiapine
the CATIE study was switched after about 10 weeks, such that the
Risperidone Ziprasidone
duration of treatment was considerably shorter in the CATIE study.
Therefore, it is not the case that atypical antipsychotics are ineffective
After two months of therapy, there were no significant differences in Z-score change from
baseline between the treatment groups with respect to the neurocognitive domains.
in the cognitive domain; rather, the significant clinical benefits are
limited to a population of patients with schizophrenia who are
Figure 5: Change in Composite Score of the Rey treatment-responsive. However, the remainder of patients who are
Auditory Verbal Learning Test
non-responsive or partially responsive face unmet needs with the
currently available drugs, necessitating switches in therapy or
Basline 6 weeks 6 months
0
additional add-on therapies in clinical practice.
34,36,37
-0.5
Direct Treatment Effects on Social Competence
-1.0
With clinical studies demonstrating that atypical antipsychotics are able
to confer reductions in cognitive impairments, there has been increasing
-1.5
interest in the shift from cognitive improvement as a predictor of
-2.0
treatment outcome to a direct measurement of functional disability in
Lower boundary
*
#
schizophrenia. After all, the ultimate treatment goal of cognitive
Mean standard deviation
-2.5 of the normal range
enhancement is to reduce overall disability. Various performance-based
-3.0
measures have been developed to evaluate the ability to work, the
Ziprasidone Olanzapine
ability to perform everyday living skills and social competence with
*p=0.014 versus 6 weeks;
#
p<0.038 versus baseline
the goal of measuring and reducing disability directly rather than
drawing inferences from impaired performance in cognitive tests and
Continued improvement was observed from baseline to six weeks and then six months with treating cognition. This was the objective of the Quetiapine Fumarate
both ziprasidone and olanzapine treatment. The improvement approached normative
standards of -0.1 standard deviation (SD). Source: Harvey et al., 2006.
35
and Risperidone in the Treatment of Patients with Schizophrenia
(QUARTZ) study, a large-scale double-blind study that randomised 673
patients to risperidone or quetiapine to investigate the effects of short-
performance. The largest overall improvement is about 0.20 SD, term treatment on neuropsychological functioning, social competence
congruent to the practice effect. Moreover, perphenazine, a rarely and social cognition in schizophrenia.
38
Neuropsychological analyses in
used antipsychotic selected as a representative for first-generation the QUARTZ study evaluated attention (Continuous Performance Test
antipsychotics, exhibited similar efficacy to olanzapine and [CPT]), visuomotor speed and executive function (Trail-making Test parts
risperidone across the different cognitive domains. These results A and B), episodic memory (Rey Auditory Verbal Learning Test [RAVLT])
raised a number of questions regarding the overall efficacy and and verbal fluency. The role-playing interactions in the Social Skills
benefits of antipsychotic treatment, or the lack thereof. Performance Assessment (SSPA) were a reflection of social
functioning,
39
while the Penn Emotional Acuity Test (PEAT) evaluating
In contrast, data from a six-month extension of a randomised, facial emotional acuity was used to determine social cognition.
40
Both
double-blind, short-term efficacy study in schizophrenia comparing treatments improved neuropsychological performance and social
ziprasidone with olanzapine showed significant improvement in cognition by the expected magnitudes of 0.2–0.4 SDs, but there was
performance across all cognitive variables and composite measures.
35
significant improvement with both treatments in the SSPA.
38
Moreover,
By selecting tests that had extensive normative data, patient improvements in episodic memory (RAVLT) and processing speed (Trail-
performance could be evaluated relative to the normative population. making Test part B) significantly correlated with improvements in social
Patients were shown to improve in terms of cognitive function to competence, thereby demonstrating for the first time ever in a
within the normal range, with some patients meeting pre-defined pharmacological study an association between cognitive improvement
criteria for normalisation in performance, from 10% of patients in the and improvements in functional disability.
Trail-making Test part B to 37% of patients in the Rey Auditory Verbal
Learning Test (RAVLT). There was a clear continued improvement in Information from pre-clinical studies is essential in directing the focus of
cognition from baseline through to six months for both atypical clinical studies. Existing pre-clinical data suggest that clinical studies
antipsychotics studied, with the mean SD approaching a score of -1.0 should investigate the effect of antipsychotics with high affinity to the
28 EUROPEAN PSYCHIATRIC REVIEW