- Email: [email protected]
Brain imaging in understanding the action of psychotropic drugs: The drugs for depression
Annales Me´dico-Psychologiques 173 (2015) 259–262
Available online at
ScienceDirect www.sciencedirect.com
Communication
Brain imaging in understanding the action of psychotropic drugs: The drugs for depression L’imagerie au service de la compre´hension de l’action des psychotropes : les antide´presseurs Guy M. Goodwin University department, Warneford hospital, Oxford OX3 7JX, United Kingdom
A R T I C L E I N F O
A B S T R A C T
Article history: Available online 18 March 2015
Objectives. – Brain imaging is now used to inform hypotheses relating not just to brain function but also the actions of drugs for depression. It can identify the relevant functional neuroanatomy of drug action and its relation to hot and cold cognition. Patients. – Patients with acute major depression or in recovery from same, in comparison with healthy controls. Results. – In the case of drugs for depression, we are limited by our understanding of the neurocognitive mechanisms involved. However, it has already been possible to show improved memory for positive descriptors for a range of drugs for depression and these are aligned in both healthy controls and patients. Brain imaging has shown corresponding early effects of drug treatment on how the amygdala responds to negative emotional stimuli. Study of cold cognition, while less developed, has attracted interest from the development of vortioxetine. Imaging studies in recovered patients and controls suggest cognitive enhancing effects of vortioxetine, which may be relevant to recovery from depression. Conclusions. – The challenge is to develop a coherent neurocognitive theory of depression that can explain or give context to the observed patterns of symptoms and their response to treatment. Brain imaging will play an important part in this programme of work. ß 2015 Elsevier Masson SAS. All rights reserved.
Keywords: Antidepressants Brain imaging Cognitive function Major depression Neuropsychology Therapeutic benefit
R E´ S U M E´
Mots cle´s : Antide´presseur Be´ne´fice the´rapeutique Fonction cognitive Imagerie ce´re´brale Me´lancolie Neuropsychologie
Objectifs. – L’imagerie ce´re´brale est maintenant utilise´e pour informer les hypothe`ses relatives non seulement pour le fonctionnement du cerveau, mais aussi les actions de me´dicaments pour la de´pression. Elle peut identifier la neuroanatomie fonctionnelle pertinente de l’action du me´dicament et de sa relation a` la cognition chaude et froide. Patients. – Les patients souffrant de de´pression majeure, par rapport aux te´moins sains. Re´sultats. – Dans le cas des me´dicaments pour la de´pression, nous sommes limite´s par notre compre´hension des me´canismes neurocognitifs implique´s. Cependant, il a de´ja` e´te´ possible de montrer une meilleure me´moire pour descripteurs positifs pour une gamme de me´dicaments pour la de´pression et ceux-ci sont aligne´s dans les deux controˆles sains et des patients. L’imagerie ce´re´brale a montre´ les effets pre´coces de traitement sur la fac¸on dont l’amygdale re´pond a` des stimuli e´motionnels ne´gatifs correspondant. L’e´tude de la cognition froide, certes moins de´veloppe´e, a suscite´ l’inte´reˆt du de´veloppement de Vortioxe´tine. Les e´tudes d’imagerie de patients gue´ris et controˆles sugge`rent des effets de l’ame´lioration cognitive de Vortioxe´tine, qui peuvent eˆtre utiles a` la re´cupe´ration de la de´pression.
E-mail address: [email protected] http://dx.doi.org/10.1016/j.amp.2015.02.005 0003-4487/ß 2015 Elsevier Masson SAS. All rights reserved.
260
G.M. Goodwin / Annales Me´dico-Psychologiques 173 (2015) 259–262
Conclusions. – Le de´fi consiste a` de´velopper une the´orie cohe´rente neurocognitives de la de´pression qui peut expliquer ou mettre en contexte les tendances observe´es de symptoˆmes et leur re´ponse au traitement. L’imagerie ce´re´brale jouera un roˆle important dans ce programme de travail. ß 2015 Elsevier Masson SAS. Tous droits re´serve´s.
1. Introduction Brain imaging has become a powerful adjunct to cognitive neuroscience. It is used to inform a range of hypotheses relating to brain function from simple perceptual activities through to complex decision-making. Its use in relation to the actions of psychotropic drugs and, in particular, drugs for depression, is still relatively under developed. However, its importance lies in three areas. The first is in identifying the relevant neural networks within which the primary actions of drugs appear to occur. Thus, it allows the identification of the relevant functional neuroanatomy of drug action. Secondly, it allows us to look in some detail at the candidate functions, which are or may be modulated by drugs for depression. These are usually classified along a continuum defined by the involvement of emotional processing of various kinds. The extremes of this dimension are, on the one hand, pure emotional processing or so-called ‘hot cognition’ and on the other, the usual classical domains of attention, memory and executive function or ‘cold cognition’. There is reasonable evidence that changes occur in acute episodes of major depression in both emotional processing and cold cognition. Moreover, some changes (notably in memory function) may be enduring and of functional significance [7]. The way in which hot and cold cognition fit together in regulating mood remains hypothetical. It is known that events, particularly major events, are triggers for the onset of mood episodes. These usually take the form of losses or disappointments. They are most prominent in first episodes of depression and become less obvious in subsequent recurrences [5]. It may also be true that the more minor events in the flow of daily life result in changes in mood that can accumulate and grow into mood instability. In bipolar patients mood instability results in movements of mood in both euphoric and depressive directions between mood episodes. In unipolar patients, the effect is less obvious and must primarily be to create depressive mood swings. The obvious hypothesis that springs from these descriptions is that depression may result from a greater sensitivity to everyday and more major events. Vulnerability to depression might reside in this greater sensitivity. Alternatively, it can be hypothesised that any relatively minor changes in daily mood must be regulated importantly by methods that are subsumed under the term ‘cognitive control’. This is a term that has a wide variety of meanings in cognitive neuroscience. The failure to have adequate automatic or conscious regulation of one’s emotions may be one of the additional factors that contribute to the risk of developing mood episodes. Whether it is either increased sensitivity or impaired cognitive control (or both) remains uncertain and relatively little studied. If feeling either excessively happy or excessively sad about real events may be something that is subject to regulation by both automatic and conscious mechanisms, how should we conceptualise and measure them. It is tempting to identify such cognitive control with central executive function but it is by no means clear that this is appropriate. The little evidence that there is derives from findings in recovered patients with unipolar disorders and the relatives of patients with bipolar disorder, both of whom appear to share increased rates of repetitive responding in a test of executive function.
Major depressive episodes are of course defined by the recurrence of a consolation of particular symptoms. Those that refer to and invoke specific changes in emotional processing include depressed mood, diminished interest or pleasure, worthlessness or excessive guilt and recurrent thoughts of death, suicidal ideation etc. Access to the ideas and memories that are implicit in the latter items could be conditioned by a depressed mood and a bias in the accessing of emotionally valenced information. In other words, such symptoms reflect emotional bias in the processing of personally sensitive information. On the other hand, the depressive syndrome also includes items reflecting cold cognition. These include psychomotor retardation, fatigue or loss of energy and a diminished ability to think or concentrate resulting in indecisiveness. All of these symptoms are observable features of the way in which patients with depression behave. Each and all could contribute to measurable failures of cold cognition which, in turn might relate quite simply to an inability to control intolerable feelings of loss, worthlessness etc. or be a mechanism whereby behavioural efforts to change the environment are impeded or even prevented. In any case, it is clear that a full syndrome requires both elements of the cognitive spectrum and either one on its own is not a convincing episode of depression. Given this provisional understanding of the neurocognitive mechanisms that underlie depression, the locus for the actions that may be the basis for the efficacy of effective treatments is likely to be elusive. In consequence, the findings that exist to this point are indicative but not definitive. Brain imaging has provided an important part of the necessary preliminary understanding. 2. Emotional processing as a target for drugs for depression The discovery of effective medicines for treating depression was initially by guided serendipity. Thus, the objective of most observational treatment studies has been dominated by a primary effect on the symptoms of depression. It is an important conceptual step to try to move beyond symptoms to study the cognitive mechanisms described previously. There is now a substantial body of work with drugs for depression that is based on the observation of their neurocognitive effects in healthy volunteers. Thus, we have a reasonable descriptive knowledge, at the level of behaviour, of the consistencies in how drugs for depression affect automatic processing or negative biases independent of the effects of depression per se. Such biases can be estimated either in the perception of social expressions on the faces of volunteers or the access to self-reference adjectives in recall or recognition tasks. Negative bias is expressed in the increased sensitivity to negative facial expressions on the one hand and negative words or descriptors on the other. The most consistent observed effect has been to increase positive bias in self-referent memory. Thus, for example, treatment with citalopram or reboxetine has a similar effect demonstrable in healthy volunteers taking either drug for one week [1]. Obviously, this effect could be the basis for the correction of prevailing negative bias in depressed patients. Indeed, a single dose of reboxetine was subsequently shown to correct and indeed to normalise the negative bias in patients being treated for major depression [3]. Moreover, this correction weakly predicted the subsequent change in symptoms at six weeks.
G.M. Goodwin / Annales Me´dico-Psychologiques 173 (2015) 259–262
These findings were initially made purely on the basis of behaviour but have now been confirmed in studies employing brain imaging. Thus, depressed patients show increased activity in the amygdala, which could be related to their hypersensitivity to negative facial information in particular. The impact of treatment is to correct this overactivity. Such normalisation was initially shown to take place over a course of treatment so it was not necessarily an early effect. But in fact, it has now been shown that the effect precedes a change in symptoms. Patients with major depression were studied after treatment for seven days with either escitalopram or placebo [6]. The sensitivity to fearful faces in the escitalopram treated patients was markedly attenuated. This normalisation of the responses in patients was comparable to the levels seen in healthy volunteers. A comparable early effect on amygdala responses of another SSRI (paroxetine) was demonstrated previously in healthy volunteers [4]. Just as changes in behaviour early in treatment predicted subsequent clinical improvement, the change in amygdala activity also predicted symptomatic changes at six weeks [6]. Such results with brain imaging increase the confidence with which we can claim an important action of SSRIs and other drugs for depression is to decrease the amygdala responses to aversive stimuli. How this automatic effect is translated into clinical improvement, which it appears to be, remains an interesting and challenging question. One possibility is that the change in emotional bias allows a relearning of normal and emotional responsiveness in the flow of every day life. To prove that this is actually the key mechanism through which the drugs work is challenging and currently unachieved.
3. Cold cognition as a target for antidepressants If cold cognition were an important mechanism implicated in the depressive syndrome, then it would be logical for improvements in cold cognition to facilitate antidepressant action or to have an antidepressant action in its own right. There have been relatively few studies of this sort to look selectively at the impact of any medication on cold cognition in depressed patients; indeed, it is only relatively recently that much interest has been taken in the fact that patients are impaired in these cognitive domains, even after recovery of a depressive episode. One study that we reported in a preliminary way at ACNP in 2014 looked at the impact of the novel treatment for depression vortioxetine compared to placebo in patients remitted from depression [2]. This study design is of interest in a number of ways. In particular, we chose an fMRI signal as the primary outcome. The particular activity was the signal during performance of the n-back test. The n-back test is a particularly challenging test of working memory. It requires subjects to monitor a stream of letters and identify when letters are repeated either one, two or three back from the current target. The test is associated with activation of prefrontal cortex while the hippocampus shows reduced activity. When compared with controls, patients show an increased prefrontal signal and reduced attenuation of the hippocampal signal [8]. Thus, the node most implicated in the circuit is in the frontal cortex where increased activity may be interpreted as increased resources for performance of an effortful task in patients who appear less able simultaneously to turn off the hippocampus. In the vortioxetine study, 48 patients remitted from depression and 48 healthy volunteers were randomized to receive either placebo or vortioxetine 20 mg daily for 2 weeks. At the end of the two-week period, the BOLD fMRI signals in both brain areas associated with the task were examined. The signal in frontal cortex was shown to be greater in remitted patients (as also described in currently depressed patients) and less attenuated in
261
the hippocampus. Vortoxetine attenuated the signal in both patients and controls for the frontal cortex and restored attenuation of signal in the hippocampus for the patient group. Task performance was unaltered although a subjective estimate of current cognitive deficits was reduced significantly in both patients and controls on vortioxetine. Thus, in the frontal region previously reported to be hyperactive in patients with depression, vortioxetine significantly reduced the neural activity whilst performing the n-back test. This occurred both in healthy volunteers or in subjects remitted from their depression. In addition, the effect in hippocampus suggests a restoration of the normal circuit shut down in this area for patients. The probable effect in pathways subserving effortful conscious processing was, accordingly to reduce the apparent metabolic demand and improve conscious appreciation of cognitive deficits. Vortioxetine is accordingly a cognitive enhancer in both groups. What is now of interest will be to determine whether its clinical profile is clearly enhanced by this property and thus, as might be predicted, that it leads either to a more complete response in patients with cold cognitive impairments or to improve cognitive function generally in most patients recovering from depression. As with the effects on cold cognition by more conventional drug treatments, the improved or normalised cold cognition may or may not contribute directly or indirectly to recovery from acute major depression. The challenge is to establish mechanisms leading to treatment response in either case. 4. Conclusions Drugs for depression are usually characterized by actions at a cellular level. There is now a substantial body of work showing that we can conceptualise their effects also at a system’s level, particularly in relation to the function of the amygdala and related neuronal circuits including prefrontal cortex. The actions of both the selective noradrenergic reuptake inhibitor reboxetine and the selective serotonergic reuptake inhibitor escitalopram have been shown in both behavioural and, in the case of escitalopram, imaging experiments to produce an effect on these circuits before there is a change in symptoms. This allows some confidence that a brain activity is present after the initiation of treatment that may be implicated in the pathway to recovery in depressed patients. This action on what is sometimes referred to as emotional processing is an important clue to understanding how antidepressants work in major depression. In addition, the very recent work using brain imaging as a primary outcome has demonstrated the likely cognitive enhancing impact of vortioxetine in both recovered patients and healthy volunteers. The contribution of brain imaging will be to further refine the questions of how treatments for depression actually work. Disclosure of interest In the last 3 years I have held grants from Servier and Lundbeck, received honoraria for speaking or chairing educational meeting from Abbvie, AstraZeneca, GSK, Lundbeck, Medscape, Servier and advised AstraZeneca, Cephalon/Teva, Lundbeck, Merck, Otsuka, P1Vital, Servier, Shire, Sunovion, and Takeda. I hold shares in P1Vital and acted as expert witness for Eli Lilly. References [1] Browning M, et al. Vortioxetine reduces BOLD signal during performance of the n-back task in subjects remitted from depression and healthy control participants. Neuropsychopharmacology 2014;39:S480. [2] Godlewska B, et al. Early changes in neural responses to emotional information predict clinical response to antidepressant treatment in depression. Int J Neuropsychopharmacol 2014;17:82.
262
G.M. Goodwin / Annales Me´dico-Psychologiques 173 (2015) 259–262
[3] Gorwood P, et al. Toxic effects of depression on brain function: impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatients. Am J Psychiatry 2008;165:731–9. [4] Harmer CJ, et al. Toward a neuropsychological theory of antidepressant drug action: increase in positive emotional bias after potentiation of norepinephrine activity. Am J Psychiatry 2003;160:990–2. [5] Harmer CJ, et al. Antidepressant drug treatment modifies the neural processing of nonconscious threat cues. Biol Psychiatry 2006;59:816–20.
[6] Harmer CJ, et al. Effect of acute antidepressant administration on negative affective bias in depressed patients. Am J Psychiatry 2009;166: 1178–84. [7] Harvey PO, et al. Cognitive control and brain resources in major depression: an fMRI study using the n-back task. Neuroimage 2005;26:860–9. [8] Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the ‘‘kindling’’ hypothesis. Am J Psychiatry 2000;157:1243–51.
Available online at
ScienceDirect www.sciencedirect.com
Communication
Brain imaging in understanding the action of psychotropic drugs: The drugs for depression L’imagerie au service de la compre´hension de l’action des psychotropes : les antide´presseurs Guy M. Goodwin University department, Warneford hospital, Oxford OX3 7JX, United Kingdom
A R T I C L E I N F O
A B S T R A C T
Article history: Available online 18 March 2015
Objectives. – Brain imaging is now used to inform hypotheses relating not just to brain function but also the actions of drugs for depression. It can identify the relevant functional neuroanatomy of drug action and its relation to hot and cold cognition. Patients. – Patients with acute major depression or in recovery from same, in comparison with healthy controls. Results. – In the case of drugs for depression, we are limited by our understanding of the neurocognitive mechanisms involved. However, it has already been possible to show improved memory for positive descriptors for a range of drugs for depression and these are aligned in both healthy controls and patients. Brain imaging has shown corresponding early effects of drug treatment on how the amygdala responds to negative emotional stimuli. Study of cold cognition, while less developed, has attracted interest from the development of vortioxetine. Imaging studies in recovered patients and controls suggest cognitive enhancing effects of vortioxetine, which may be relevant to recovery from depression. Conclusions. – The challenge is to develop a coherent neurocognitive theory of depression that can explain or give context to the observed patterns of symptoms and their response to treatment. Brain imaging will play an important part in this programme of work. ß 2015 Elsevier Masson SAS. All rights reserved.
Keywords: Antidepressants Brain imaging Cognitive function Major depression Neuropsychology Therapeutic benefit
R E´ S U M E´
Mots cle´s : Antide´presseur Be´ne´fice the´rapeutique Fonction cognitive Imagerie ce´re´brale Me´lancolie Neuropsychologie
Objectifs. – L’imagerie ce´re´brale est maintenant utilise´e pour informer les hypothe`ses relatives non seulement pour le fonctionnement du cerveau, mais aussi les actions de me´dicaments pour la de´pression. Elle peut identifier la neuroanatomie fonctionnelle pertinente de l’action du me´dicament et de sa relation a` la cognition chaude et froide. Patients. – Les patients souffrant de de´pression majeure, par rapport aux te´moins sains. Re´sultats. – Dans le cas des me´dicaments pour la de´pression, nous sommes limite´s par notre compre´hension des me´canismes neurocognitifs implique´s. Cependant, il a de´ja` e´te´ possible de montrer une meilleure me´moire pour descripteurs positifs pour une gamme de me´dicaments pour la de´pression et ceux-ci sont aligne´s dans les deux controˆles sains et des patients. L’imagerie ce´re´brale a montre´ les effets pre´coces de traitement sur la fac¸on dont l’amygdale re´pond a` des stimuli e´motionnels ne´gatifs correspondant. L’e´tude de la cognition froide, certes moins de´veloppe´e, a suscite´ l’inte´reˆt du de´veloppement de Vortioxe´tine. Les e´tudes d’imagerie de patients gue´ris et controˆles sugge`rent des effets de l’ame´lioration cognitive de Vortioxe´tine, qui peuvent eˆtre utiles a` la re´cupe´ration de la de´pression.
E-mail address: [email protected] http://dx.doi.org/10.1016/j.amp.2015.02.005 0003-4487/ß 2015 Elsevier Masson SAS. All rights reserved.
260
G.M. Goodwin / Annales Me´dico-Psychologiques 173 (2015) 259–262
Conclusions. – Le de´fi consiste a` de´velopper une the´orie cohe´rente neurocognitives de la de´pression qui peut expliquer ou mettre en contexte les tendances observe´es de symptoˆmes et leur re´ponse au traitement. L’imagerie ce´re´brale jouera un roˆle important dans ce programme de travail. ß 2015 Elsevier Masson SAS. Tous droits re´serve´s.
1. Introduction Brain imaging has become a powerful adjunct to cognitive neuroscience. It is used to inform a range of hypotheses relating to brain function from simple perceptual activities through to complex decision-making. Its use in relation to the actions of psychotropic drugs and, in particular, drugs for depression, is still relatively under developed. However, its importance lies in three areas. The first is in identifying the relevant neural networks within which the primary actions of drugs appear to occur. Thus, it allows the identification of the relevant functional neuroanatomy of drug action. Secondly, it allows us to look in some detail at the candidate functions, which are or may be modulated by drugs for depression. These are usually classified along a continuum defined by the involvement of emotional processing of various kinds. The extremes of this dimension are, on the one hand, pure emotional processing or so-called ‘hot cognition’ and on the other, the usual classical domains of attention, memory and executive function or ‘cold cognition’. There is reasonable evidence that changes occur in acute episodes of major depression in both emotional processing and cold cognition. Moreover, some changes (notably in memory function) may be enduring and of functional significance [7]. The way in which hot and cold cognition fit together in regulating mood remains hypothetical. It is known that events, particularly major events, are triggers for the onset of mood episodes. These usually take the form of losses or disappointments. They are most prominent in first episodes of depression and become less obvious in subsequent recurrences [5]. It may also be true that the more minor events in the flow of daily life result in changes in mood that can accumulate and grow into mood instability. In bipolar patients mood instability results in movements of mood in both euphoric and depressive directions between mood episodes. In unipolar patients, the effect is less obvious and must primarily be to create depressive mood swings. The obvious hypothesis that springs from these descriptions is that depression may result from a greater sensitivity to everyday and more major events. Vulnerability to depression might reside in this greater sensitivity. Alternatively, it can be hypothesised that any relatively minor changes in daily mood must be regulated importantly by methods that are subsumed under the term ‘cognitive control’. This is a term that has a wide variety of meanings in cognitive neuroscience. The failure to have adequate automatic or conscious regulation of one’s emotions may be one of the additional factors that contribute to the risk of developing mood episodes. Whether it is either increased sensitivity or impaired cognitive control (or both) remains uncertain and relatively little studied. If feeling either excessively happy or excessively sad about real events may be something that is subject to regulation by both automatic and conscious mechanisms, how should we conceptualise and measure them. It is tempting to identify such cognitive control with central executive function but it is by no means clear that this is appropriate. The little evidence that there is derives from findings in recovered patients with unipolar disorders and the relatives of patients with bipolar disorder, both of whom appear to share increased rates of repetitive responding in a test of executive function.
Major depressive episodes are of course defined by the recurrence of a consolation of particular symptoms. Those that refer to and invoke specific changes in emotional processing include depressed mood, diminished interest or pleasure, worthlessness or excessive guilt and recurrent thoughts of death, suicidal ideation etc. Access to the ideas and memories that are implicit in the latter items could be conditioned by a depressed mood and a bias in the accessing of emotionally valenced information. In other words, such symptoms reflect emotional bias in the processing of personally sensitive information. On the other hand, the depressive syndrome also includes items reflecting cold cognition. These include psychomotor retardation, fatigue or loss of energy and a diminished ability to think or concentrate resulting in indecisiveness. All of these symptoms are observable features of the way in which patients with depression behave. Each and all could contribute to measurable failures of cold cognition which, in turn might relate quite simply to an inability to control intolerable feelings of loss, worthlessness etc. or be a mechanism whereby behavioural efforts to change the environment are impeded or even prevented. In any case, it is clear that a full syndrome requires both elements of the cognitive spectrum and either one on its own is not a convincing episode of depression. Given this provisional understanding of the neurocognitive mechanisms that underlie depression, the locus for the actions that may be the basis for the efficacy of effective treatments is likely to be elusive. In consequence, the findings that exist to this point are indicative but not definitive. Brain imaging has provided an important part of the necessary preliminary understanding. 2. Emotional processing as a target for drugs for depression The discovery of effective medicines for treating depression was initially by guided serendipity. Thus, the objective of most observational treatment studies has been dominated by a primary effect on the symptoms of depression. It is an important conceptual step to try to move beyond symptoms to study the cognitive mechanisms described previously. There is now a substantial body of work with drugs for depression that is based on the observation of their neurocognitive effects in healthy volunteers. Thus, we have a reasonable descriptive knowledge, at the level of behaviour, of the consistencies in how drugs for depression affect automatic processing or negative biases independent of the effects of depression per se. Such biases can be estimated either in the perception of social expressions on the faces of volunteers or the access to self-reference adjectives in recall or recognition tasks. Negative bias is expressed in the increased sensitivity to negative facial expressions on the one hand and negative words or descriptors on the other. The most consistent observed effect has been to increase positive bias in self-referent memory. Thus, for example, treatment with citalopram or reboxetine has a similar effect demonstrable in healthy volunteers taking either drug for one week [1]. Obviously, this effect could be the basis for the correction of prevailing negative bias in depressed patients. Indeed, a single dose of reboxetine was subsequently shown to correct and indeed to normalise the negative bias in patients being treated for major depression [3]. Moreover, this correction weakly predicted the subsequent change in symptoms at six weeks.
G.M. Goodwin / Annales Me´dico-Psychologiques 173 (2015) 259–262
These findings were initially made purely on the basis of behaviour but have now been confirmed in studies employing brain imaging. Thus, depressed patients show increased activity in the amygdala, which could be related to their hypersensitivity to negative facial information in particular. The impact of treatment is to correct this overactivity. Such normalisation was initially shown to take place over a course of treatment so it was not necessarily an early effect. But in fact, it has now been shown that the effect precedes a change in symptoms. Patients with major depression were studied after treatment for seven days with either escitalopram or placebo [6]. The sensitivity to fearful faces in the escitalopram treated patients was markedly attenuated. This normalisation of the responses in patients was comparable to the levels seen in healthy volunteers. A comparable early effect on amygdala responses of another SSRI (paroxetine) was demonstrated previously in healthy volunteers [4]. Just as changes in behaviour early in treatment predicted subsequent clinical improvement, the change in amygdala activity also predicted symptomatic changes at six weeks [6]. Such results with brain imaging increase the confidence with which we can claim an important action of SSRIs and other drugs for depression is to decrease the amygdala responses to aversive stimuli. How this automatic effect is translated into clinical improvement, which it appears to be, remains an interesting and challenging question. One possibility is that the change in emotional bias allows a relearning of normal and emotional responsiveness in the flow of every day life. To prove that this is actually the key mechanism through which the drugs work is challenging and currently unachieved.
3. Cold cognition as a target for antidepressants If cold cognition were an important mechanism implicated in the depressive syndrome, then it would be logical for improvements in cold cognition to facilitate antidepressant action or to have an antidepressant action in its own right. There have been relatively few studies of this sort to look selectively at the impact of any medication on cold cognition in depressed patients; indeed, it is only relatively recently that much interest has been taken in the fact that patients are impaired in these cognitive domains, even after recovery of a depressive episode. One study that we reported in a preliminary way at ACNP in 2014 looked at the impact of the novel treatment for depression vortioxetine compared to placebo in patients remitted from depression [2]. This study design is of interest in a number of ways. In particular, we chose an fMRI signal as the primary outcome. The particular activity was the signal during performance of the n-back test. The n-back test is a particularly challenging test of working memory. It requires subjects to monitor a stream of letters and identify when letters are repeated either one, two or three back from the current target. The test is associated with activation of prefrontal cortex while the hippocampus shows reduced activity. When compared with controls, patients show an increased prefrontal signal and reduced attenuation of the hippocampal signal [8]. Thus, the node most implicated in the circuit is in the frontal cortex where increased activity may be interpreted as increased resources for performance of an effortful task in patients who appear less able simultaneously to turn off the hippocampus. In the vortioxetine study, 48 patients remitted from depression and 48 healthy volunteers were randomized to receive either placebo or vortioxetine 20 mg daily for 2 weeks. At the end of the two-week period, the BOLD fMRI signals in both brain areas associated with the task were examined. The signal in frontal cortex was shown to be greater in remitted patients (as also described in currently depressed patients) and less attenuated in
261
the hippocampus. Vortoxetine attenuated the signal in both patients and controls for the frontal cortex and restored attenuation of signal in the hippocampus for the patient group. Task performance was unaltered although a subjective estimate of current cognitive deficits was reduced significantly in both patients and controls on vortioxetine. Thus, in the frontal region previously reported to be hyperactive in patients with depression, vortioxetine significantly reduced the neural activity whilst performing the n-back test. This occurred both in healthy volunteers or in subjects remitted from their depression. In addition, the effect in hippocampus suggests a restoration of the normal circuit shut down in this area for patients. The probable effect in pathways subserving effortful conscious processing was, accordingly to reduce the apparent metabolic demand and improve conscious appreciation of cognitive deficits. Vortioxetine is accordingly a cognitive enhancer in both groups. What is now of interest will be to determine whether its clinical profile is clearly enhanced by this property and thus, as might be predicted, that it leads either to a more complete response in patients with cold cognitive impairments or to improve cognitive function generally in most patients recovering from depression. As with the effects on cold cognition by more conventional drug treatments, the improved or normalised cold cognition may or may not contribute directly or indirectly to recovery from acute major depression. The challenge is to establish mechanisms leading to treatment response in either case. 4. Conclusions Drugs for depression are usually characterized by actions at a cellular level. There is now a substantial body of work showing that we can conceptualise their effects also at a system’s level, particularly in relation to the function of the amygdala and related neuronal circuits including prefrontal cortex. The actions of both the selective noradrenergic reuptake inhibitor reboxetine and the selective serotonergic reuptake inhibitor escitalopram have been shown in both behavioural and, in the case of escitalopram, imaging experiments to produce an effect on these circuits before there is a change in symptoms. This allows some confidence that a brain activity is present after the initiation of treatment that may be implicated in the pathway to recovery in depressed patients. This action on what is sometimes referred to as emotional processing is an important clue to understanding how antidepressants work in major depression. In addition, the very recent work using brain imaging as a primary outcome has demonstrated the likely cognitive enhancing impact of vortioxetine in both recovered patients and healthy volunteers. The contribution of brain imaging will be to further refine the questions of how treatments for depression actually work. Disclosure of interest In the last 3 years I have held grants from Servier and Lundbeck, received honoraria for speaking or chairing educational meeting from Abbvie, AstraZeneca, GSK, Lundbeck, Medscape, Servier and advised AstraZeneca, Cephalon/Teva, Lundbeck, Merck, Otsuka, P1Vital, Servier, Shire, Sunovion, and Takeda. I hold shares in P1Vital and acted as expert witness for Eli Lilly. References [1] Browning M, et al. Vortioxetine reduces BOLD signal during performance of the n-back task in subjects remitted from depression and healthy control participants. Neuropsychopharmacology 2014;39:S480. [2] Godlewska B, et al. Early changes in neural responses to emotional information predict clinical response to antidepressant treatment in depression. Int J Neuropsychopharmacol 2014;17:82.
262
G.M. Goodwin / Annales Me´dico-Psychologiques 173 (2015) 259–262
[3] Gorwood P, et al. Toxic effects of depression on brain function: impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatients. Am J Psychiatry 2008;165:731–9. [4] Harmer CJ, et al. Toward a neuropsychological theory of antidepressant drug action: increase in positive emotional bias after potentiation of norepinephrine activity. Am J Psychiatry 2003;160:990–2. [5] Harmer CJ, et al. Antidepressant drug treatment modifies the neural processing of nonconscious threat cues. Biol Psychiatry 2006;59:816–20.
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