Skip to main content
×
×
Home

Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action

  • Catherine J. Harmer (a1), Guy M. Goodwin (a1) and Philip J. Cowen (a1)
Abstract
Background

The neuropharmacological actions of antidepressants are well characterised but our understanding of how these changes translate into improved mood are still emerging.

Aims

To investigate whether actions of antidepressant drugs on emotional processing are a mediating factor in the effects of these drugs in depression.

Method

We examined key published findings that explored the effects of antidepressants on behavioural and functional magnetic resonance imaging (fMRI) measures of emotional processing.

Results

Negative emotional bias has been reliably associated with depression. Converging results suggest that antidepressants modulate emotional processing and increase positive emotional processing much earlier than effects on mood. These changes in emotional processing are associated with neural modulation in limbic and prefrontal circuitry.

Conclusions

Antidepressants may work in a manner consistent with cognitive theories of depression. Antidepressants do not act as direct mood enhancers but rather change the relative balance of positive to negative emotional processing, providing a platform for subsequent cognitive and psychological reconsolidation.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action
      Available formats
      ×
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action
      Available formats
      ×
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action
      Available formats
      ×
Copyright
Corresponding author
Catherine Harmer, Warneford Hospital, Oxford OX3 7JX, UK. Email: Catherine.harmer@psych.ox.ac.uk
Footnotes
Hide All

Declaration of interest

G.M.G. and P.J.C. have been members of advisory boards of pharmaceutical companies marketing antidepressants. C.J.H. has acted as a paid consultant for Lundbeck and Merck Sharp & Dohme and is on the advisory board of P1vital.

Footnotes
References
Hide All
1 Frazer, A, Benmansour, S. Delayed pharmacological effects of antidepressants. Mol Psychiatry 2002; 7 (suppl. 1): S238.
2 Manji, HK, Quiroz, JA, Sporn, J, Payne, JL, Denicoff, K, Gray, A, et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry 2003; 53: 707–42.
3 Satel, SL, Nelson, JC. Stimulants in the treatment of depression: a critical overview. J Clin Psychiatry 1989; 50: 241–9.
4 Beck, AT, Rush, AJ, Shaw, BF, Emery, G. Cognitive Therapy of Depression. Guilford, 1979.
5 Wilson, SJ, Bell, C, Coupland, NJ, Nutt, DJ. Sleep changes during long-term treatment of depression with fluvoxamine – a home-based study. Psychopharmacology 2000; 149: 360–5.
6 Matt, G, Vacquez, C, Campbell, WK. Mood congruent recall of affectively toned stimuli: a meta-analytical review. Clin Psychol Rev 1992; 12: 227–55.
7 Leppanen, JM. Emotional information processing in mood disorders: a review of behavioral and neuroimaging findings. Curr Opin Psychiatry 2006; 19: 34–9.
8 Gur, RC, Erwin, RJ, Gur, RE, Zwil, AS, Heimberg, C, Kraemer, HC. Facial emotion discrimination: II. Behavioral findings in depression. Psychiatry Res 1992; 42: 241–51.
9 Mogg, K, Bradley, BP, Williams, R. Attentional bias in anxiety and depression: the role of awareness. Br J Clin Psychol 1995; 34: 1736.
10 Surguladze, S, Brammer, MJ, Keedwell, P, Giampietro, V, Young, AW, Travis, MJ, et al. A differential pattern of neural response toward sad versus happy facial expressions in major depressive disorder. Biol Psychiatry 2005; 57: 201–9.
11 Fu, CH, Williams, SC, Cleare, AJ, Brammer, MJ, Walsh, ND, Kim, J, et al. Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study. Arch Gen Psychiatry 2004; 61: 877–89.
12 Lawrence, NS, Williams, AM, Surguladze, S, Giampietro, V, Brammer, MJ, Andrew, C, et al. Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression. Biol Psychiatry 2004; 55: 578–87.
13 Fu, CH, Williams, SC, Brammer, MJ, Suckling, J, Kim, J, Cleare, AJ, et al. Neural responses to happy facial expressions in major depression following antidepressant treatment. Am J Psychiatry 2007; 164: 599607.
14 Vuilleumier, P, Driver, J. Modulation of visual processing by attention and emotion: windows on causal interactions between human brain regions. Philos Trans R Soc Lond B Biol Sci 2007; 362: 837–55.
15 Elliott, R, Rubinsztein, JS, Sahakian, BJ, Dolan, RJ. The neural basis of moodcongruent processing biases in depression. Arch Gen Psychiatry 2002; 59: 597604.
16 Chan, SW, Goodwin, GM, Harmer, CJ. Highly neurotic never-depressed students have negative biases in information processing. Psychol Med 2007; 37: 1281–91.
17 Hayward, G, Goodwin, GM, Cowen, PJ, Harmer, CJ. Low-dose tryptophan depletion in recovered depressed patients induces changes in cognitive processing without depressive symptoms. Biol Psychiatry 2005; 57: 517–24.
18 Mannie, ZN, Bristow, GC, Harmer, CJ, Cowen, PJ. Impaired emotional categorisation in young people at increased familial risk of depression. Neuropsychologia 2007; 45: 2975–80.
19 Joormann, J, Talbot, L, Gotlib, IH. Biased processing of emotional information in girls at risk for depression. J Abnorm Psychol 2007; 116: 135–43.
20 Haas, BW, Omura, K, Constable, RT, Canli, T. Emotional conflict and neuroticism: personality-dependent activation in the amygdala and subgenual anterior cingulate. Behav Neurosci 2007; 121: 249–56.
21 Harmer, CJ, Shelley, NC, Cowen, PJ, Goodwin, GM. Increased positive versus negative affective perception and memory in healthy volunteers following selective serotonin and norepinephrine reuptake inhibition. Am J Psychiatry 2004; 161: 1256–63.
22 Harmer, CJ, Bhagwagar, Z, Perrett, DI, Vollm, BA, Cowen, PJ, Goodwin, GM. Acute SSRI administration affects the processing of social cues in healthy volunteers. Neuropsychopharmacology 2003; 28: 148–52.
23 Harmer, CJ, Hill, SA, Taylor, MJ, Cowen, PJ, Goodwin, GM. Towards a neuropsychological theory of antidepressant drug action: potentiation of norepinephrine activity increases positive emotional bias. Am J Psychiatry 2003; 160: 990–2.
24 Browning, M, Reid, C, Cowen, PJ, Goodwin, GM, Harmer, C. A single dose of citalopram increases fear recognition in healthy subjects. J Psychopharmacol 2007; 21: 684–90.
25 Gibbs, AA, Naudts, KH, Spencer, EP, David, AS. The role of dopamine in attentional and memory biases for emotional information. Am J Psychiatry 2007; 164: 1603–9.
26 Lawrence, AD, Calder, AJ, McGowan, SW, Grasby, PM. Selective disruption of the recognition of facial expressions of anger. Neuroreport 2002; 13: 881–4.
27 Knutson, B, Wolkowitz, OM, Cole, SW, Chan, T, Moore, EA, Johnson, RC, et al. Selective alteration of personality and social behavior by serotonergic intervention. Am J Psychiatry 1998; 155: 373–9.
28 Tse, WS, Bond, AJ. Reboxetine promotes social bonding in healthy volunteers. J Psychopharmacol 2003; 17: 189–95.
29 Tse, WS, Bond, AJ. Serotonergic intervention affects both social dominance and affiliative behaviour. Psychopharmacology 2002; 161: 324–30.
30 Harmer, CJ, Mackay, CE, Reid, CB, Cowen, PJ, Goodwin, GM. Antidepressant drug treatment modifies the neural processing of nonconscious threat cues. Biol Psychiatry 2006; 59: 816–20.
31 Norbury, R, Mackay, CE, Cowen, PJ, Goodwin, GM, Harmer, CJ. Short-term antidepressant treatment and facial processing: functional magnetic resonance imaging study. Br J Psychiatry 2007; 190: 531–2.
32 Whalen, PJ, Shin, LM, Somerville, LH, McLean, AA, Kim, H. Functional neuroimaging studies of the amygdala in depression. Semin Clin Neuropsychiatry 2002; 7: 234–42.
33 Norbury, R, Mackay, CE, Cowen, PJ, Goodwin, GM, Harmer, CJ. The effects of reboxetine on emotional processing in healthy volunteers: an fMRI study. Mol Psychiatry 2008; 13: 1011–20.
34 MacLeod, C, Rutherford, E, Campbell, L, Ebsworthy, G, Holker, L. Selective attention and emotional vulnerability: assessing the causal basis of their association through the experimental manipulation of attentional bias. J Abnorm Psychol 2002; 111: 107–23.
35 Grillon, C, Levenson, J, Pine, DS. A single dose of the selective serotonin reuptake inhibitor citalopram exacerbates anxiety in humans: a fearpotentiated startle study. Neuropsychopharmacology 2007; 32: 225–31.
36 Kent, JM, Coplan, JD, Gorman, JM. Clinical utility of the selective serotonin reuptake inhibitors in the spectrum of anxiety. Biol Psychiatry 1998; 44: 812–24.
37 Burghardt, NS, Sullivan, GM, McEwen, BS, Gorman, JM, LeDoux, JE. The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: a comparison with tianeptine. Biol Psychiatry 2004; 55: 1171–8.
38 National Institute for Health and Clinical Excellence. Anxiety: Management of Anxiety (Panic Disorder, with or without Agoraphobia, and Generalised Anxiety Disorder) in Adults in Primary, Secondary and Community Care. NICE Guideline CG22 (Amended). NICE, 2007.
39 Davidson, RJ, Irwin, W, Anderle, MJ, Kalin, NH. The neural substrates of affective processing in depressed patients treated with venlafaxine. Am J Psychiatry 2003; 160: 6475.
40 Schaefer, HS, Putnam, KM, Benca, RM, Davidson, RJ. Event-related functional magnetic resonance imaging measures of neural activity to positive social stimuli in pre- and post-treatment depression. Biol Psychiatry 2006; 60: 974–86.
41 Longmore, RJ, Worrell, M. Do we need to challenge thoughts in cognitive behavior therapy? Clin Psychol Rev 2007; 27: 173–87.
42 Kennedy, SH, Konarski, JZ, Segal, ZV, Lau, MA, Bieling, PJ, McIntyre, RS, et al. Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. Am J Psychiatry 2007; 164: 778–88.
43 Simon, J, Pilling, S, Burbeck, R, Goldberg, D. Treatment options in moderate and severe depression: decision analysis supporting a clinical guideline. Br J Psychiatry 2006; 189: 494501.
44 Hafizi, S, Chandra, P, Cowen, PJ. Neurokinin-1 receptor antagonists as novel antidepressants: trials and tribulations. Br J Psychiatry 2007; 191: 282–4.
45 Chandra, P, Hafizi, S, Massey-Chase, R, Goodwin, G, Cowen, P, Harmer, C. NK1 receptor antagonism and emotional processing in healthy volunteers. J Psychopharmacol 2009; Apr 7 (Epub ahead of print).
46 Tranter, R, Bell, D, Gutting, P, Harmer, C, Healy, D, Anderson, IM. The effect of serotonergic and noradrenergic antidepressants on face emotion processing in depressed patients. J Affect Disord 2009; Feb 26 (Epub ahead of print).
47 Critchley, HD, Lewis, PA, Orth, M, Josephs, O, Deichmann, R, Trimble, MR, et al. Vagus nerve stimulation for treatment-resistant depression: behavioral and neural effects on encoding negative material. Psychosom Med 2007; 69: 1722.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The British Journal of Psychiatry
  • ISSN: 0007-1250
  • EISSN: 1472-1465
  • URL: /core/journals/the-british-journal-of-psychiatry
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 8
Total number of PDF views: 265 *
Loading metrics...

Abstract views

Total abstract views: 1036 *
Loading metrics...

* Views captured on Cambridge Core between 2nd January 2018 - 23rd June 2018. This data will be updated every 24 hours.

Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action

  • Catherine J. Harmer (a1), Guy M. Goodwin (a1) and Philip J. Cowen (a1)
Submit a response

eLetters

No eLetters have been published for this article.

×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *