human psychopharmacology Hum. Psychopharmacol Clin Exp 2013; 28: 535–537. Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.2360
EDITORIAL
On ‘cognitive dysfunction’ as a novel target for antidepressant treatment Cognitive problems are recognised symptoms in current diagnostic criteria for major depressive disorder (MDD), but the objective effects of antidepressant treatment on cognitive function in patients with depression have not been studied extensively (Lee et al., 2012). ‘Cognition’ is a very broad term, which includes learning and memory, attention and executive function. It is known that previously depressed patients who are assessed whilst in the euthymic state, and their healthy first-degree relatives, show evidence of impaired cognition (Bora et al., 2013). These findings suggest that impaired cognition during a major depressive episode may not simply result from the presence of low mood, but might instead reflect a separate process itself contributing to the origin and maintenance of depression. It has long been known that certain tricyclic antidepressants - with their often marked anticholinergic and antihistaminic effects - can impair cognition, leading to problems such as decreased driving performance (Theunissen et al., 2013). But the effects of antidepressant drugs on cognition in depressed patients may be two-fold: first, lifting of mood should lead indirectly to an improvement in cognitive performance; and second, the pharmacological properties of an antidepressant may have direct effects, either improving or worsening cognitive function. Certain antidepressants may be associated with improved cognitive function, both in patients with late-onset depression and in younger adults (under 65 years): and in some studies there is evidence to show that the enhancements in cognition are separate from the overall improvement in mood (Raskin et al., 2007). One way to ascertain whether antidepressants exert direct beneficial or detrimental cognitive effects is to ascertain their effects in non-depressed individuals: for example a study in healthy volunteers administered intravenous citalopram (a selective serotonin reuptake inhibitor, SSRI) or placebo showed an acute improvement in long-term memory in those participants that received citalopram, indicating that the pharmacological mechanism of the drug could directly influence Copyright © 2013 John Wiley & Sons, Ltd.
cognition (Harmer et al., 2002). There is also evidence that the SSRI fluoxetine can improve memory in older patients with mild cognitive impairment, in the absence of symptomatic depression, further indicating that antidepressants may directly modulate cognition (Mowla et al., 2007). However, Knorr et al. administered escitalopram to the healthy first-degree relatives of depressed patients, and did not identify any substantial alterations in measures of cognitive performance (Knorr et al., 2011). The findings of studies of antidepressants on cognitive function in depressed patients suggest that only some measures of cognitive performance are improved during antidepressant treatment. For example, in an early double-blind comparison of the effects of the selective noradrenaline reuptake inhibitor reboxetine and the SSRI paroxetine over 8 weeks, Ferguson et al. (2003) found that depressed patients showed a significant improvement in the continuity of attention and combined speed after 8 weeks of taking reboxetine, though this only represented a trend towards improvement, when compared to placebo; paroxetine was associated with a significant improvement in combined speed after 2 weeks, but after 8 weeks this had declined to baseline scores. Improvement in cognitive function did not correlate with the improvement in mood, suggesting that reboxetine had an effect on cognition beyond that related to depressive symptoms (Ferguson et al., 2003). Subsequently Constant et al. (2005) showed that 3 weeks of treatment with the SSRI sertraline in MDD patients (with a minimum of mild depression) was associated with improvements in both attention and executive function (controls were healthy volunteers who were given no treatment). In this study, depressed patients were subgrouped into those with more and less severe anxiety symptoms: the more anxious patients had a slower reaction time in the Stroop test (illustrating poorer executive function) but showed a greater improvement in reaction time following sertraline treatment, suggesting that anxiety symptoms may be a useful marker for improving cognition in MDD patients (Constant et al., 2005). Furthermore, Raskin et al. (2007) studied the effects of the
536
b. impey and d. s. baldwin
serotonin-noradrenaline reuptake inhibitor (SNRI) duloxetine in depressed patients aged 65 years or older, with evidence of no more than mild cognitive impairment on the Mini Mental State Examination (Folstein et al., 1975) and showed that 7 weeks of treatment was associated with improved verbal learning and memory, although there were no notable changes in attention, executive function or working memory (Raskin et al., 2007). More recently, Hinkelmann et al. (2012) showed that acute treatment (3 weeks) with the SSRI escitalopram in MDD patients was associated with improvements in both verbal and non-verbal memory, when compared to placebo: though selective attention and concentration, the speed of cognitive processing, and measures of executive functioning were unchanged in either group (Hinkelmann et al., 2012). These findings support those of Herrera-Guzmán et al. (2010) who found that 24 weeks of escitalopram treatment was associated with improvements in verbal and visual working memory, sustained attention, inhibition of automated responses, set-shifting and planning, when compared to a control group; a comparison group undergoing treatment with the SNRI duloxetine showed a similar pattern and extent of change in cognition as was seen during escitalopram treatment (Herrera-Guzmán et al., 2010). In addition, Chang et al. (2012) gave either the SNRI venlafaxine or the SSRI fluoxetine to MDD patients for 6 weeks, and noted improvements in attention, motor speed and accuracy, and executive function (Chang et al., 2012). The novel antidepressant vortioxetine acts on the 5-HT transporter (SERT) and directly on 5-HT receptors, with antagonist effects at 5-HT3, 5-HT7 and 5-HT1D receptors and an agonist effect at 5-HT1A and 5-HT1B receptors. A recent pre-clinical investigation found it was able to reverse memory deficits resulting from 5-HT depletion, probably through its antagonism of 5-HT3 and agonism of 5-HT1A receptors (du Jardin et al., 2013). In addition, Katona et al. (2012) evaluated the effects of 8 weeks of double-blind treatment with duloxetine or vortioxetine in elderly depressed patients without cognitive impairment. Patients given duloxetine and vortioxetine showed significant improvements in learning and memory when compared to placebo, but only patients given vortioxetine showed an improvement in processing speed, executive function and attention when compared to placebo (Katona et al., 2012). It is possible that the effects of antidepressant on cognitive performance might be enhanced by accompanying psychological interventions or ‘cognitive training’, as has been seen in the augmentation of antipsychotic drug Copyright © 2013 John Wiley & Sons, Ltd.
treatment in patients with schizophrenia This has been illustrated in a meta-analysis by McGurk et al. (2007), who focussed on the use of drill and practice – a method which aims to improve cognitive processing through increasingly difficult exercises. They showed that attention, processing speed, working memory, verbal learning and memory, reasoning and problem solving all improved significantly following cognitive training in schizophrenia (McGurk et al., 2007). A recent study in depressed adults assessed the ability of computerised cognitive training to affect both cognitive function and depression, and also evaluated the patient’s opinion of any coincident change in daily functioning. They found that following cognitive training, patients showed improved executive function and attention and also a decline in depressive symptom severity, although the improvements in cognition did not correlate significantly with the self-reported improvement in function (Preiss et al., 2013). Taken together, these studies show that a number of antidepressant drugs are able to improve some aspects of cognitive function. However nearly all studies involved antidepressant administration for relatively short periods, and as such it is uncertain whether these medications exert sustained beneficial cognitive effects. In addition, it is currently unclear whether a measured enhancement in a few aspects of cognition translates into noticeable improvements in everyday functioning. There is a need to achieve consensus on the most reliable and sensitive measures of cognitive performance during antidepressant treatment, and to assess the effects of long-term antidepressant administration or treatment. CONFLICT OF INTEREST DSB is the Editor-in-Chief of Human Psychopharmacology. DSB has received research funding from and attended an advisory board organised by H. Lundbeck, A/S, the manufacturers of vortioxetine. BI declares no potential conflict of interest. REFERENCES Bora E, Harrison BJ, Yücel M, et al. 2013. Cognitive impairment in euthymic major depressive disorder: a meta-analysis. Psychol Med 43(10): 2017–2026. Chang HH, Lee IH, Gean PW, et al. 2012. Treatment response and cognitive impairment in major depression: association with C-reactive protein. Brain Behav Immun 26(1): 90–95. Constant EL, Adam S, Gillain B, et al. 2005. Effects of sertraline on depressive symptoms and attentional and executive functions in major depression. Depress Anxiety 21(2): 78–89. Ferguson JM, Wesnes KA, Schwartz GE. 2003. Reboxetine versus paroxetine versus placebo: effects on cognitive functioning in depressed patients. Int Clin Psychopharmacol 18(1): 9–14.
Hum. Psychopharmacol Clin Exp 2013; 28: 535–537. DOI: 10.1002/hup
editorial Folstein MF, Folstein SE, McHugh PR. 1975. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3): 189–198. Harmer CJ, Bhagwagar Z, Cowen PJ, et al. 2002. Acute administration of citalopram facilitates memory consolidation in healthy volunteers. Psychopharmacology (Berl) 163(1): 106–110. Herrera-Guzmán I, Herrera-Abarca JE, Gudayol-Ferré E, et al. 2010. Effects of selective serotonin reuptake and dual serotonergicnoradrenergic reuptake treatments on attention and executive functions in patients with major depressive disorder. Psychiatry Res 177(3): 323–329. Hinkelmann K, Moritz S, Botzenhardt J, et al. 2012. Changes in cortisol secretion during antidepressive treatment and cognitive improvement in patients with major depression: a longitudinal study. Psychoneuroendocrinology 37(5): 685–692. du Jardin KG, Jensen JB, Sanchez C, et al. 2013. Vortioxetine dosedependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: A potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism. Eur Neuropsychopharmacol. doi: 10.1016/j.euroneuro.2013.07.001[published Online First: Epub Date]|. Katona C, Hansen T, Olsen CK. 2012. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol 27(4): 215–223. Knorr U, Vinberg M, Gade A, et al. 2011. A randomised trial of the effect of escitalopram versus placebo on cognitive function in healthy first-d e g r e e relatives of patients with depression. Ther Adv Psychopharm 1: 133–144. Lee RS, Hermens DF, Porter MA, et al. 2012. A meta-analysis of cognitive deficits in first-episode Major Depressive Disorder. J Affect Disord 140(2): 113–124.
Copyright © 2013 John Wiley & Sons, Ltd.
537
McGurk SR, Twamley EW, Sitzer DI, et al. 2007. A meta-analysis of cognitive remediation in schizophrenia. Am J Psychiatry;164(12): 1791–802. Mowla A, Mosavinasab M, Pani A. 2007. Does fluoxetine have any effect on the cognition of patients with mild cognitive impairment? A double-blind, placebo-controlled, clinical trial. J Clin Psychopharmacol 27(1): 67–70. Preiss M, Shatil E, Cermáková R, et al. 2013. Personalized cognitive training in unipolar and bipolar disorder: a study of cognitive functioning. Front Hum Neurosci 7:108. Raskin J, Wiltse CG, Siegal A, et al. 2007. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psychiatry 164(6): 900–909. Theunissen EL, Street D, Højer AM, et al. 2013. A randomized trial on the acute and steady-state effects of a new antidepressant, vortioxetine (Lu AA21004), on actual driving and cognition. Clin Pharmacol Ther 93(6): 493–501.
Bethan Impey Clinical and Experimental Sciences Academic Unit, University of Southampton Faculty of Medicine David S. Baldwin Clinical and Experimental Sciences Academic Unit, University of Southampton Faculty of Medicine
Hum. Psychopharmacol Clin Exp 2013; 28: 535–537. DOI: 10.1002/hup
EDITORIAL
On ‘cognitive dysfunction’ as a novel target for antidepressant treatment Cognitive problems are recognised symptoms in current diagnostic criteria for major depressive disorder (MDD), but the objective effects of antidepressant treatment on cognitive function in patients with depression have not been studied extensively (Lee et al., 2012). ‘Cognition’ is a very broad term, which includes learning and memory, attention and executive function. It is known that previously depressed patients who are assessed whilst in the euthymic state, and their healthy first-degree relatives, show evidence of impaired cognition (Bora et al., 2013). These findings suggest that impaired cognition during a major depressive episode may not simply result from the presence of low mood, but might instead reflect a separate process itself contributing to the origin and maintenance of depression. It has long been known that certain tricyclic antidepressants - with their often marked anticholinergic and antihistaminic effects - can impair cognition, leading to problems such as decreased driving performance (Theunissen et al., 2013). But the effects of antidepressant drugs on cognition in depressed patients may be two-fold: first, lifting of mood should lead indirectly to an improvement in cognitive performance; and second, the pharmacological properties of an antidepressant may have direct effects, either improving or worsening cognitive function. Certain antidepressants may be associated with improved cognitive function, both in patients with late-onset depression and in younger adults (under 65 years): and in some studies there is evidence to show that the enhancements in cognition are separate from the overall improvement in mood (Raskin et al., 2007). One way to ascertain whether antidepressants exert direct beneficial or detrimental cognitive effects is to ascertain their effects in non-depressed individuals: for example a study in healthy volunteers administered intravenous citalopram (a selective serotonin reuptake inhibitor, SSRI) or placebo showed an acute improvement in long-term memory in those participants that received citalopram, indicating that the pharmacological mechanism of the drug could directly influence Copyright © 2013 John Wiley & Sons, Ltd.
cognition (Harmer et al., 2002). There is also evidence that the SSRI fluoxetine can improve memory in older patients with mild cognitive impairment, in the absence of symptomatic depression, further indicating that antidepressants may directly modulate cognition (Mowla et al., 2007). However, Knorr et al. administered escitalopram to the healthy first-degree relatives of depressed patients, and did not identify any substantial alterations in measures of cognitive performance (Knorr et al., 2011). The findings of studies of antidepressants on cognitive function in depressed patients suggest that only some measures of cognitive performance are improved during antidepressant treatment. For example, in an early double-blind comparison of the effects of the selective noradrenaline reuptake inhibitor reboxetine and the SSRI paroxetine over 8 weeks, Ferguson et al. (2003) found that depressed patients showed a significant improvement in the continuity of attention and combined speed after 8 weeks of taking reboxetine, though this only represented a trend towards improvement, when compared to placebo; paroxetine was associated with a significant improvement in combined speed after 2 weeks, but after 8 weeks this had declined to baseline scores. Improvement in cognitive function did not correlate with the improvement in mood, suggesting that reboxetine had an effect on cognition beyond that related to depressive symptoms (Ferguson et al., 2003). Subsequently Constant et al. (2005) showed that 3 weeks of treatment with the SSRI sertraline in MDD patients (with a minimum of mild depression) was associated with improvements in both attention and executive function (controls were healthy volunteers who were given no treatment). In this study, depressed patients were subgrouped into those with more and less severe anxiety symptoms: the more anxious patients had a slower reaction time in the Stroop test (illustrating poorer executive function) but showed a greater improvement in reaction time following sertraline treatment, suggesting that anxiety symptoms may be a useful marker for improving cognition in MDD patients (Constant et al., 2005). Furthermore, Raskin et al. (2007) studied the effects of the
536
b. impey and d. s. baldwin
serotonin-noradrenaline reuptake inhibitor (SNRI) duloxetine in depressed patients aged 65 years or older, with evidence of no more than mild cognitive impairment on the Mini Mental State Examination (Folstein et al., 1975) and showed that 7 weeks of treatment was associated with improved verbal learning and memory, although there were no notable changes in attention, executive function or working memory (Raskin et al., 2007). More recently, Hinkelmann et al. (2012) showed that acute treatment (3 weeks) with the SSRI escitalopram in MDD patients was associated with improvements in both verbal and non-verbal memory, when compared to placebo: though selective attention and concentration, the speed of cognitive processing, and measures of executive functioning were unchanged in either group (Hinkelmann et al., 2012). These findings support those of Herrera-Guzmán et al. (2010) who found that 24 weeks of escitalopram treatment was associated with improvements in verbal and visual working memory, sustained attention, inhibition of automated responses, set-shifting and planning, when compared to a control group; a comparison group undergoing treatment with the SNRI duloxetine showed a similar pattern and extent of change in cognition as was seen during escitalopram treatment (Herrera-Guzmán et al., 2010). In addition, Chang et al. (2012) gave either the SNRI venlafaxine or the SSRI fluoxetine to MDD patients for 6 weeks, and noted improvements in attention, motor speed and accuracy, and executive function (Chang et al., 2012). The novel antidepressant vortioxetine acts on the 5-HT transporter (SERT) and directly on 5-HT receptors, with antagonist effects at 5-HT3, 5-HT7 and 5-HT1D receptors and an agonist effect at 5-HT1A and 5-HT1B receptors. A recent pre-clinical investigation found it was able to reverse memory deficits resulting from 5-HT depletion, probably through its antagonism of 5-HT3 and agonism of 5-HT1A receptors (du Jardin et al., 2013). In addition, Katona et al. (2012) evaluated the effects of 8 weeks of double-blind treatment with duloxetine or vortioxetine in elderly depressed patients without cognitive impairment. Patients given duloxetine and vortioxetine showed significant improvements in learning and memory when compared to placebo, but only patients given vortioxetine showed an improvement in processing speed, executive function and attention when compared to placebo (Katona et al., 2012). It is possible that the effects of antidepressant on cognitive performance might be enhanced by accompanying psychological interventions or ‘cognitive training’, as has been seen in the augmentation of antipsychotic drug Copyright © 2013 John Wiley & Sons, Ltd.
treatment in patients with schizophrenia This has been illustrated in a meta-analysis by McGurk et al. (2007), who focussed on the use of drill and practice – a method which aims to improve cognitive processing through increasingly difficult exercises. They showed that attention, processing speed, working memory, verbal learning and memory, reasoning and problem solving all improved significantly following cognitive training in schizophrenia (McGurk et al., 2007). A recent study in depressed adults assessed the ability of computerised cognitive training to affect both cognitive function and depression, and also evaluated the patient’s opinion of any coincident change in daily functioning. They found that following cognitive training, patients showed improved executive function and attention and also a decline in depressive symptom severity, although the improvements in cognition did not correlate significantly with the self-reported improvement in function (Preiss et al., 2013). Taken together, these studies show that a number of antidepressant drugs are able to improve some aspects of cognitive function. However nearly all studies involved antidepressant administration for relatively short periods, and as such it is uncertain whether these medications exert sustained beneficial cognitive effects. In addition, it is currently unclear whether a measured enhancement in a few aspects of cognition translates into noticeable improvements in everyday functioning. There is a need to achieve consensus on the most reliable and sensitive measures of cognitive performance during antidepressant treatment, and to assess the effects of long-term antidepressant administration or treatment. CONFLICT OF INTEREST DSB is the Editor-in-Chief of Human Psychopharmacology. DSB has received research funding from and attended an advisory board organised by H. Lundbeck, A/S, the manufacturers of vortioxetine. BI declares no potential conflict of interest. REFERENCES Bora E, Harrison BJ, Yücel M, et al. 2013. Cognitive impairment in euthymic major depressive disorder: a meta-analysis. Psychol Med 43(10): 2017–2026. Chang HH, Lee IH, Gean PW, et al. 2012. Treatment response and cognitive impairment in major depression: association with C-reactive protein. Brain Behav Immun 26(1): 90–95. Constant EL, Adam S, Gillain B, et al. 2005. Effects of sertraline on depressive symptoms and attentional and executive functions in major depression. Depress Anxiety 21(2): 78–89. Ferguson JM, Wesnes KA, Schwartz GE. 2003. Reboxetine versus paroxetine versus placebo: effects on cognitive functioning in depressed patients. Int Clin Psychopharmacol 18(1): 9–14.
Hum. Psychopharmacol Clin Exp 2013; 28: 535–537. DOI: 10.1002/hup
editorial Folstein MF, Folstein SE, McHugh PR. 1975. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3): 189–198. Harmer CJ, Bhagwagar Z, Cowen PJ, et al. 2002. Acute administration of citalopram facilitates memory consolidation in healthy volunteers. Psychopharmacology (Berl) 163(1): 106–110. Herrera-Guzmán I, Herrera-Abarca JE, Gudayol-Ferré E, et al. 2010. Effects of selective serotonin reuptake and dual serotonergicnoradrenergic reuptake treatments on attention and executive functions in patients with major depressive disorder. Psychiatry Res 177(3): 323–329. Hinkelmann K, Moritz S, Botzenhardt J, et al. 2012. Changes in cortisol secretion during antidepressive treatment and cognitive improvement in patients with major depression: a longitudinal study. Psychoneuroendocrinology 37(5): 685–692. du Jardin KG, Jensen JB, Sanchez C, et al. 2013. Vortioxetine dosedependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: A potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism. Eur Neuropsychopharmacol. doi: 10.1016/j.euroneuro.2013.07.001[published Online First: Epub Date]|. Katona C, Hansen T, Olsen CK. 2012. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol 27(4): 215–223. Knorr U, Vinberg M, Gade A, et al. 2011. A randomised trial of the effect of escitalopram versus placebo on cognitive function in healthy first-d e g r e e relatives of patients with depression. Ther Adv Psychopharm 1: 133–144. Lee RS, Hermens DF, Porter MA, et al. 2012. A meta-analysis of cognitive deficits in first-episode Major Depressive Disorder. J Affect Disord 140(2): 113–124.
Copyright © 2013 John Wiley & Sons, Ltd.
537
McGurk SR, Twamley EW, Sitzer DI, et al. 2007. A meta-analysis of cognitive remediation in schizophrenia. Am J Psychiatry;164(12): 1791–802. Mowla A, Mosavinasab M, Pani A. 2007. Does fluoxetine have any effect on the cognition of patients with mild cognitive impairment? A double-blind, placebo-controlled, clinical trial. J Clin Psychopharmacol 27(1): 67–70. Preiss M, Shatil E, Cermáková R, et al. 2013. Personalized cognitive training in unipolar and bipolar disorder: a study of cognitive functioning. Front Hum Neurosci 7:108. Raskin J, Wiltse CG, Siegal A, et al. 2007. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psychiatry 164(6): 900–909. Theunissen EL, Street D, Højer AM, et al. 2013. A randomized trial on the acute and steady-state effects of a new antidepressant, vortioxetine (Lu AA21004), on actual driving and cognition. Clin Pharmacol Ther 93(6): 493–501.
Bethan Impey Clinical and Experimental Sciences Academic Unit, University of Southampton Faculty of Medicine David S. Baldwin Clinical and Experimental Sciences Academic Unit, University of Southampton Faculty of Medicine
Hum. Psychopharmacol Clin Exp 2013; 28: 535–537. DOI: 10.1002/hup
