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Department of Psychiatry, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA
Correspondence: Dr Sergio Paradiso, University of Iowa Carver College of Medicine, Department of Psychiatry, 200 Hawkins Drive, W278 GH, Iowa City, IA 52242, USA. Tel: +1 (319) 384 9248; fax: +1 (319) 353 8656; email: sergio-paradiso{at}uiowa.edu
Funding detailed in Acknowledgements.
* Presented in part at the annual meeting of the American Neuropsychiatry
Association, La Jolla, California, 18–21 February 2006. 
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Aims To examine the effect of antidepressants on executive function after stroke.
Method Forty-seven patients who had had a stroke during the prior 6 months received 12 weeks of antidepressant treatment in double-blind placebo-controlled fashion, followed by assessment of executive function at the end of treatment and after 2 years.
Results No significant group effect was found at the end of treatment. However, 21 months after the end of treatment the placebo group showed deterioration of executive function, whereas the active treatment group showed clear and significant improvement independent of depressive symptoms (F=12.1, d.f.=1,45, P= 0.001).
Conclusions Antidepressant treatment fosters long-term improvement of executive function following stroke. This phenomenon is consistent with a reorganisation of neuronal networks associated with prefrontal functions based on modulation of monoaminergic neurotransmission and the activity of neurotrophins.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Antidepressant treatment improves outcome following stroke, independently of depression. Nortriptyline and fluoxetine improve activities of daily living (Narushima & Robinson, 2003) and mortality (Jorge et al, 2003), and sertraline improves morbidity (Rasmussen et al, 2003). Antidepressants may exert outcome-improving effects on the brain in at least two ways: one is through modulation of cortical-striato-pallido-thalamo-cortical pathways subsequent to action on the raphe nuclei, locus ceruleus and ventral tegmental area (Alexopoulos et al, 2000); another is through reorganisation of neural circuitry favoured by their activity on brain-derived neurotrophic factor (BDNF) (Saarelainen et al, 2003).
This evidence prompted our study hypothesis that antidepressants improve frontal executive function following stroke. This hypothesis has not been tested before. The positive effect of treatment with antidepressants on the cognitive abilities of older adults (Allard et al, 2003) and the identification of similar mechanisms of executive deficit in late life and stroke (Coffey et al, 1988a,b) further supported the rationale behind this study. We predicted that antidepressant treatment would improve executive dysfunction independently of depression.
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METHOD |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Patients taking antidepressants discontinued them for a 2-week wash-out period before the study. Written consent was obtained in accordance with institutional review board requirements. Ninety-two patients entered the double-blind placebo-controlled phase and 69 completed it (Fig. 1).
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2=3.04, P=0.08).
Clinical and background variables of patients not included in the analysis
were not significantly different from those of participants included in the
analyses. Data from 47 patients were analysed, 30 of these patients were
treated with either nortriptyline (n=11) or fluoxetine
(n=19), and 17 received placebo.
Treatment protocol
Patients were randomly assigned to 12 weeks of either fluoxetine,
nortriptyline or placebo, unless there was a definite contra-indication.
Nortriptyline was chosen because it is reported to be effective in post-stroke
depression (Lipsey et al,
1984); fluoxetine was chosen because it is a commonly used
selective serotonin reuptake inhibitor with the advantage of a long half-life.
Nortriptyline was not given to patients with cardiac abnormalities, and
fluoxetine was contraindicated in patients with intracerebral haemorrhage.
Eight patients had a contraindication to nortriptyline and nine to fluoxetine:
these patients were randomly reassigned to the alternative active medication
or to placebo. Thus, 85% of the patients were randomly assigned to
nortriptyline, fluoxetine or placebo. All patients were randomly assigned to
either active or placebo medication.
The dosages of nortriptyline were 25 mg per day for the first week, 50 mg per day for weeks 2 and 3, then 75 mg per day for weeks 4–6 and 100 mg per day for the final 6 weeks. Dosages of fluoxetine were 10 mg per day for the first 3 weeks, 20 mg per day for weeks 4–6, then 30 mg per day for weeks 7–9 and 40 mg per day for the final 3 weeks. In nine patients the dosages had to be decreased owing to severe side-effects; five were being treated with nortriptyline and four with fluoxetine. Reduction of dosage was achieved in double-blind fashion. All the patients were fully compliant with their medication regimen throughout the treatment period. After completion of the treatment phase of the study, all the medications were discontinued.
Assessment
The initial neuropsychological examination took place after the completion
of the 12-week double-blind phase. This was followed by a second evaluation 21
months after the end of active treatment.
The neurological examination was conducted by a neurologist using the National Institutes of Health (NIH) Stroke Scale (Brott et al, 1989). Severity of depression was assessed using the 17-item version of the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960). Overall cognitive functioning was assessed with the Mini-Mental State Examination (MMSE; Folstein et al, 1975). All assessments were conducted by examiners masked to the participants' background conditions.
The following tests of executive function constituted the primary outcome variables: the Controlled Oral Word Association (COWA; Benton, 1967) test measured initiation and psychomotor speed; the Wisconsin Card Sorting Test Perseverative Errors (WCST–PE; Grant & Berg, 1948) and the Wechsler Adult Intelligence Scale–Revised (WAIS–R; Wechsler, 1981) Similarities sub-tests measured conceptualisation and problem-solving; and the WAIS–R Arithmetic and Digit Span sub-tests measured attention and working memory.
Neuroimaging
Computerised tomography or magnetic resonance scans were obtained and
evaluated for anatomical location and lesion volume by a neuroradiologist or a
neurologist unaware of the psychiatric findings. Lesion volume was estimated
using the ratio of the largest cross-sectional area of the lesion to the area
of the brain slice that included the body of the lateral ventricles
(Robinson et al,
1986).
Statistical analysis
Between-group comparisons were made using means, standard deviations and
repeated-measures analysis of variance (ANOVA). Frequency distributions were
compared using the chi-squared test. Individual executive function scores were
transformed into standardised z scores which were combined into an
`executive index'. The follow-up executive index scores were based on
z scores calculated using the baseline means and standard deviations.
Changes between the initial and follow-up measures were evaluated by change
scores, where positive scores showed improvement and negative scores showed
deterioration. Multiple linear regression was used to examine the potential
contribution of clinical factors to executive improvement. All tests were
two-tailed and significance was set at P<0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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In the period between the initial and follow-up evaluations, some patients were given antidepressants by their treating physicians. Type, dosage and duration of all prescribed medications were recorded. The frequency and the duration of antidepressant treatment in the two groups were not significantly different (Table 1). Additionally, there was no significant group difference in MMSE scores at the initial evaluation (active treatment, mean=27.5, s.d.=0.71; placebo group, mean=27.0, s.d.=0.95; P=0.66) and at follow-up (active treatment, mean=27.8, s.d.=0.85; placebo group, mean=25.6, s.d.=0.95; P=0.12). There was no significant group difference in neurological and radiological variables (Table 2).
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Executive index
At the completion of the treatment phase, executive performance showed no
statistically significant between-group effect (F=0.01, d.f.=1,45,
P=0.91).
A significant time-by-group interaction was found between the initial and follow-up evaluation. This was true for both efficacy analysis (i.e. analysing only patients who completed the 24-month follow-up: F=13.1, d.f.=1,34, P=0.001) and intention-to-treat (ITT) analysis (i.e. analysing all patients who enrolled in the treatment study, with missing data interpolated based on actual observations using the last observation carried forward method: F=12.1, d.f.=1,45, P=0.001). Patients given active treatment showed an improvement in executive performance after 21 months, whereas patients given placebo showed a decline (Fig. 2).
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Individual tests of executive function
Participants' performance on the individual tests composing the executive
index was also examined (Fig.
3). The COWA and WCST–PE tests showed significant treatment
effects compared with placebo in change scores (COWA test, efficacy analysis:
F=6.46, d.f.=1,34, P=0.02; COWA test, ITT analysis:
F=6.22, d.f.=1,45, P=0.02; WCST–PE, efficacy analysis:
F=7.19, d.f.=1,34, P=0.01, WCST–PE ITT analysis:
F=6.87, d.f.=1,45, P=0.01). The WAIS–R Similarities,
Digit Span and Arithmetic sub-tests showed the same direction of change, but
failed to reach statistical significance
(Fig. 3).
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The final model predicting executive function consisted of active treatment or placebo, age, past psychiatric history, neurological impairment and total lesion volume (F(5,25)=3.91, P<0.05). The only factor that showed a significant independent effect was active treatment or placebo (F(1,25)=14.9, P<0.01) (Table 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Caveats
Before discussing these findings, some factors that might have influenced
our results should be acknowledged. The majority of patients were high-school
or college-educated, White, married and belonged to Hollingshead social class
I to III (I is the highest, V is the lowest). Therefore, the results may not
be applicable to all stroke patients. As expected in studies examining elderly
people, follow-up evaluations could not be obtained for all patients. This may
limit generalisation of our findings to people willing or able to receive
follow-up evaluations. Some patients were prescribed antidepressants during
the naturalistic follow-up, and a small number of patients were reassigned to
the alternative active treatment or placebo for medical reasons; these factors
might have introduced bias (although naturalistic antidepressant treatment was
not an independent predictor of recovery). Finally, there was no
neuropsychological assessment to ensure the two groups had equivalent levels
of executive function prior to treatment; hence, despite randomisation, this
might have influenced the results.
Clinical implications
The findings in this study have important implications for the
neuropsychiatry of stroke and rehabilitation medicine. Antidepressants
administered within 6 months of stroke appear to improve long-term executive
function outcome. This effect is two-fold. As can be observed in
Fig. 1, antidepressants both
improve and prevent decline of executive function. How can this interesting
and clinically important phenomenon be explained?
Mechanisms
Frontal cortical–subcortical circuits
Five frontal cortical–subcortical circuits – motor, oculomotor,
dorsolateral prefrontal, lateral orbital frontal, and anterior cingulate
– subserve distinct motor and cognitive abilities
(Alexander et al,
1986). All circuits originate in the prefrontal cortex, project to
the striatum, synapse at the level of the globus pallidus, substantia nigra
and thalamus, and finally return to the prefrontal cortex, forming closed
loops – the cortical-striato-pallido-thalamo-cortical (CSPTC) pathway.
The dorsolateral prefrontal, orbitofrontal, and anterior cingulate cortical
circuits subserve both executive (Drewe,
1974; Baker et al,
1996) and affective functions (Baxter et al,
1985,
1989;
Drevets et al, 1992;
Baker et al, 1996;
Elliott et al, 1997).
They can be modulated by the activity of monoaminergic nuclei, including the
raphe nuclei, the locus ceruleus and the ventral tegmental area
(Alexopoulos et al,
2000), which are sites of action of antidepressant medications.
Thus, the mechanism of executive function recovery may be the modulation of
monoaminergic nuclei exerting effects on CSPTC circuits.
Neurogenesis
Another possible mechanism stems from the association of chronic
antidepressant administration and neurogenesis. Neurogenesis in the adult
brain is generally thought to be restricted to germinal centres in the
subventricular zone and the hippocampal/dentate gyrus
(Peterson, 2002). Chronic
administration of antidepressants enhances the development of immature neurons
and promotes the survival and function of adult neurons by enhancing BDNF and
its receptor trkB, resulting in functional and anatomical changes. Activation
of BDNF and trkB receptor has been shown to be required for antidepressants to
induce behavioural effects (Saarelainen
et al, 2003), and has been posited as an explanation for
the delayed treatment effect of antidepressants
(Nibuya et al, 1995).
Although there has been no demonstration of neurogenesis in the prefrontal
cortex, chronic antidepressant treatment induces activation of trkB receptor
in the prefrontal cortex and is responsible for the sensitisation to the
effects of BDNF (Saarelainen et
al, 2003). Neurotrophins, particularly BDNF, have been shown
to regulate neurite outgrowth (membrane-enclosed protrusions of neuronal cell
cytoplasm), synaptic plasticity and the selection of functional connections in
the central nervous system in general
(Katz & Shatz, 1996;
McAllister et al,
1999). Consistent with these findings is the recent notion that
chronic administration of antidepressants prevents stress-induced reduction of
BDNF (Manji & Duman, 2001;
McEwen & Lasley, 2003;
Brown et al, 2004).
The finding in our study may make the study of neurotrophin-mediated
mechanisms of improved executive function worth pursuing in greater
detail.
Future studies
Our study has shown that early treatment with antidepressants following
stroke has a remote positive effect on recovery and prevention of decline in
executive function. Monoaminergic modulation of frontal executive functions
and/or enhancement of neuronal plasticity and reorganisation of limbic and
frontal structures may underlie this phenomenon. Our findings require
confirmation in further studies, which might also explore whether any
particular antidepressant is to be preferred, and the optimal time, duration
and dosage of treatment.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Received for publication April 5, 2006. Revision received August 16, 2006. Accepted for publication September 29, 2006.
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