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The response to sulpiride in major depression before and after cognitive behavioural therapy: D2 receptor function

  • Caroline Bell (a1), Shamina Bhika (a1), Richard Porter (a1), Chris Frampton (a1), Janet Carter (a1), Virginia McIntosh (a1), Jenny Jordan (a1) and Peter Joyce (a1)...



Previous studies have suggested that antidepressant treatment of depression may potentiate dopamine transmission through increased sensitivity of postsynaptic D2 receptors.


D2 receptor function was assessed in 24 patients with major depression before and 16 patients after 16 weeks of treatment with cognitive behavioural therapy (CBT) using a challenge with a selective D2 antagonist, sulpiride. Four hundred milligrams of sulpiride was administered orally on two test days and response was measured by the change in prolactin levels and changes in self-rating scale measures of mood, anxiety and pleasure.


The prolactin response to sulpiride (as measured by the maximum prolactin level) was significantly increased after CBT (z = −2.792, p = 0.005). Sulpiride resulted in an improvement on mood ratings on both test days, but after CBT, this effect was significantly diminished as measured by the Profile of Mood States score (t = −2.27, p = 0.038).


After 16 weeks of CBT, we detected an enhanced prolactin response to sulpiride, suggesting an increased sensitivity of D2 receptor functioning.


Corresponding author

Dr Caroline Bell, Department of Psychological Medicine, University of Otago, PO Box 4345, Christchurch, New Zealand. Tel: +64 3 372 0400; Fax: +64 3 372 0407; E-mail:


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1.D’Aquila, PS, Collu, M, Gessa, GL, Serra, G. The role of dopamine in the mechanism of action of antidepressant drugs. Eur J Pharmacol 2000;405:365373.
2.Dunlop, BW, Nemeroff, CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 2007;64:327337.
3.Cummings, JL. Depression and Parkinson’s disease: a review. Am J Psychiatry 1992;149:443454.
4.Rogers, MA, Bradshaw, JL, Pantelis, C, Phillips, JG. Frontostriatal deficits in unipolar major depression. Brain Res Bull 1998;47:297310.
5.Bressan, RA, Costa, DC, Jones, HM, Ell, PJ, Pilowsky, LS. Typical antipsychotic drugs – D(2) receptor occupancy and depressive symptoms in schizophrenia. Schizophr Res 2002;56:3136.
6.Goldberg, JF, Burdick, KE, Endick, CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry 2004;161:564566.
7.Tremblay, LK, Naranjo, CA, Graham, SJet al. Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. Arch Gen Psychiatry 2005;62:12281236.
8.Tremblay, LK, Naranjo, CA, Cardenas, L, Herrmann, N, Busto, UE. Probing brain reward system function in major depressive disorder: altered response to dextroamphetamine. Arch Gen Psychiatry 2002;59:409416.
9.Papp, M, Klimek, V, Willner, P. Parallel changes in dopamine D2 receptor binding in limbic forebrain associated with chronic mild stress-induced anhedonia and its reversal by imipramine. Psychopharmacology (Berl) 1994;115:441446.
10.Willner, P, Muscat, R, Papp, M. Chronic mild stress-induced anhedonia: a realistic animal model of depression. Neurosci Biobehav Rev 1992;16:525534.
11.Willner, P, Lappas, S, Cheeta, S, Muscat, R. Reversal of stress-induced anhedonia by the dopamine receptor agonist, pramipexole. Psychopharmacology 1994;115:454462.
12.Kapur, S, Mann, JJ. Role of the dopaminergic system in depression. Biol Psychiatry 1992;32:117.
13.Maj, J, Papp, M, Skuza, G, Bigajska, K, Zazula, M. The influence of repeated treatment with imipramine, (+)- and (-)-oxaprotiline on behavioural effects of dopamine D-1 and D-2 agonists. J Neural Transm 1989;76:2938.
14.Willner, P. Dopamine and depression. In: Di Chiara, G, ed. Handbook of experimental pharmacology: dopamine in the CNS. Berlin: Springer, 2002;387416.
15.Collu, M, Poggiu, AS, Devoto, P, Serra, G. Behavioural sensitization of mesolimbic dopamine D2 receptors in chronic fluoxetine-treated rats. Eur J Pharmacol 1997;322:123127.
16.Smith, TD, Kuczenski, R, George-Friedman, K, Malley, JD, Foote, SL. In vivo microdialysis assessment of extracellular serotonin and dopamine levels in awake monkeys during sustained fluoxetine administration. Synapse 2000;38:460470.
17.D’Aquila, PS, Peana, AT, Panin, F, Grixoni, C, Cossu, M, Serra, G. Reversal of antidepressant-induced dopaminergic behavioural supersensitivity after long-term chronic imipramine withdrawal. Eur J Pharmacol 2003;458:129134.
18.Sampson, D, Willner, P, Muscat, R. Reversal of antidepressant action by dopamine antagonists in an animal model of depression. Psychopharmacology 1991;104:491495.
19.Willner, P, Papp, M. Animal models to detect antidepressants: are new strategies necessary to detect new agents? In: Skolnick, P, ed. Antidepressants: new pharmacological strategies. Totowa: Humana, 1997;213234.
20.Mendels, J, Frazer, A, Fitzgerald, RG, Ramsey, TA, Stokes, JW. Biogenic amine metabolites in cerebrospinal fluid of depressed and manic patients. Science 1972;175:13801382.
21.Korf, J, Van Praag, HM. Retarded depression and the dopamine metabolism. Psychopharmacologia 1971;19:199203.
22.Post, RM, Kotin, J, Goodwin, FK, Gordon, EK. Psychomotor activity and cerebrospinal fluid amine metabolites in affective illness. Am J Psychiatry 1973;130:6772.
23.Lambert, G, Johansson, M, Agren, H, Friberg, P. Reduced brain norepinephrine and dopamine release in treatment-refractory depressive illness: evidence in support of the catecholamine hypothesis of mood disorders. Arch Gen Psychiatry 2000;57:787793.
24.Verbeeck, WJC. The prolactin response to sulpiride in major depression: the role of the D2 receptor in depression. Eur Neuropsychopharmacol 2001;11:215220.
25.Joyce, PR, Donald, RA, Livesey, JH, Abbott, RM. The prolactin response to metoclopramide is increased in depression and in euthymic rapid cycling bipolar patients. Biol Psychiatry 1987;22:508512.
26.McPherson, H, Walsh, A, Silverstone, T. Growth hormone and prolactin response to apomorphine in bipolar and unipolar depression. J Affect Disord 2003;76:121125.
27.Anderson, IM, Cowen, PJ. Prolactin response to the dopamine antagonist, metoclopramide, in depression. Biol Psychiatry 1991;30:313316.
28.D’Haenen, HA, Bossuyt, A. Dopamine D2 receptors in depression measured with single photon emission computed tomography. Biol Psychiatry 1994;35:128132.
29.Shah, PJ, Ogilvie, AD, Goodwin, GM, Embeier, KP. Clinical and psychometric correlates of dopamine D2 binding in depression. Psychol Med 1997;27:12471256.
30.Ebert, D, Feistel, H, Loew, T, Pirner, A. Dopamine and depression – striatal dopamine D2 receptor SPECT before and after antidepressant therapy. Psychopharmacology 1996;126:9194.
31.Klimke, A, Larisch, R, Janz, A, Vosberg, H, Muller-Gartner, HW, Gaebel, W. Dopamine D2 receptor binding before and after treatment of major depression measured by [123I]IBZM SPECT. Psychiatry Res 1999;90:91101.
32.Parsey, RV, Oquendo, MA, Zea-Ponce, Yet al. Dopamine D2 receptor availability and amphetamine-induced dopamine release in unipolar depression. Biol Psychiatry 2001;50:313322.
33.Meyer, JH, McNeely, HE, Sagrati, Set al. Elevated putamen D2 receptor binding potential in major depression with motor retardation: an [11C]raclopride positron emission tomography study. Am J Psychiatry 2006;163:15941602.
34.Ebert, D, Kaschka, W, Stegbauer, P, Schrell, U. Prolactin response to sulpiride before and after sleep deprivation in depression. Biol Psychiatry 1993;33:666669.
35.Larish, R, Klimke, A, Vosberg, H, Loffler, S, Gaebel, W, Muller-Gartner, HW. In vivo evidence for the involvement of dopamine-D2 receptors in striatum and anterior cingulated gyrus in major depression. Neuroimage 1997;5:251260.
36.Willner, P, Hale, AS, Argyropoulos, S. Dopaminergic mechanism of antidepressant action in depressed patients. J Affect Disord 2005;86:3745. Koning, P, de Vries, MH. A comparison of the neuro-endocrinological and temperature effects of DU 29894, flesinoxan, sulpiride and haloperidol in normal volunteers. Br J Clin Pharmacol 1995;39:714.
38.First, MB, Spitzer, RL, Gibbon, M, Williams, JB. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I/P, version 2.0, 8/98 revision). New York: Biometrics Research Department, New York State Psychiatric Institute, 1998.
39.Hamilton, M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:5662.
40.Montgomery, SA, Asberg, M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382389.
41.McNair, DM, Lorr, M, Droppleman, LF. Manual of the Profile of Mood States. San Diego: Educational and Industrial Testing Service, 1971.
42.Spielberger, C, Gorsuch, R, Lushene, R. Manual for the State Trait Anxiety Inventory. Palo Alto: Consulting Psychologists Press, 1970.
43.Heinz, A, Schmidt, LG, Reischies, FM. Anhedonia in schizophrenic, depressed, or alcohol-dependent patients-neurobiological correlates. Pharmacopsychiatry 1994;27:710.
44.Snaith, RP, Hamilton, M, Morley, S, Humayan, A, Hargreaves, D, Trigwell, P. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry 1995;167:99103.
45.Gerlach, J, Korsgaard, S, Clemmesen, Pet al. The St. Hans Rating Scale for extrapyramidal syndromes: reliability and validity. Acta Psychiatr Scand 1993;87:244252.
46.von Bahr, C, Wiesel, FA, Movin, Get al. Neuroendocrine responses to single oral doses of remoxipride and sulpiride in healthy female and male volunteers. Psychopharmacology 1991;103:443448.
47.Mehta, MA, Sahakian, BJ, McKenna, PJ, Robbins, TW. Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson’s disease. Psychopharmacology 1999;146:162174.
48.Ueda, N, Yoshimura, R, Shinkai, K, Nakamura, J. Plasma levels of catecholamine metabolites predict the response to sulpiride or fluvoxamine in major depression. Pharmacopsychiatry 2002;35:175181.
49.Bocchetta, A, Bernardi, F, Burrai, C, Pedditzi, M, Del Zompo, M. A double-blind study of L-sulpiride versus amitriptyline in lithium-maintained bipolar depressives. Acta Psychiatr Scand 1993;88:434439.
50.Standish-Barry, HM, Bouras, N, Bridges, PK, Watson, JP. A randomized double blind group comparative study of sulpiride and amitriptyline in affective disorder. Psychopharmacology 1983;81:258260.
51.Pani, L, Gessa, GL. The substituted benzamides and their clinical potential on dysthymia and on the negative symptoms of schizophrenia. Mol Psychiatry 2002;7:247253.
52.Beck, AT, Shaw, BF, Emery, G. Cognitive therapy of depression. New York: Guilford Press, 1979.



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