CNS Spectr. 2008;13(7):561-565
Faculty Affiliation and Disclosure
Dr. Stein is professor in and chair of the Department of Psychiatry and Mental Health at the University of Cape Town in South Africa, and is also on faculty at the Mount Sinai School of Medicine in New York City.
Faculty Disclosures: Dr. Stein has received grant support/honoraria from AstraZeneca, Eli Lilly, GlaxoSmithKline, Lundbeck A/S, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, and Wyeth.
Funding/Support: Dr. Stein receives support from the Medical Research Council of South Africa.
Authors’ note: This case is based on an amalgam of the author’s experience.
The heterogeneity of major depression suggests that multiple neurocircuits and neurochemicals are involved in its pathogenesis. Anhedonia and psychomotor symptoms are, however, particularly characteristic features of major depression and may provide insights into its underlying psychobiology. Importantly, these symptoms appear to be mediated by dopaminergic mesolimbic and mesostriatal projections, the function of which is, in turn, influenced by key gene variants and environment stressors. Indeed, there is growing evidence of the way in which the dopaminergic system is associated with cognitive-affective disturbances in depression, and provides a useful target for therapeutic interventions. At the same time, a range of other systems are likely to contribute to the psychobiology of this condition.
Rachel is a 43-year-old woman who presented for treatment to her primary care physician. She complained of depressed mood, not finding pleasure in her life, and of feeling slower and slower. She had a range of other classical symptoms of depression, including poor concentration, decreased appetite, and insomnia. On mental status examination, her speech was slowed, and there was evidence of psychomotor retardation. Her primary care physician initiated bupropion, increasing the dosage to 100 mg TID. After several weeks of treatment, she demonstrated a good response to treatment. Rachel was particularly delighted to report that she was enjoying life again, and had the sense that she was moving around more quickly and more responsively.
Depression is a heterogenous condition characterized by multiple symptoms and subtypes. Different symptoms (eg, poor concentration, disturbed sleep) and subtypes (eg, melancholic, seasonal) are likely mediated by different neurocircuitry and neurochemistry,1-3 and may or may not be present, in any particular individual with depression. Depression may be characterized by an increase or a decrease in certain of its symptoms (eg, hyperphagia, hypophagia), further complicating attempts to explore its psychobiology.
Nevertheless, anhedonia—or loss of pleasure—appears to be a particularly central feature of major depression.4-6 Reward is mediated by dopaminergic projections to the nucleus accumbens, suggesting that mesolimbic neurocircuitry plays a crucial role in the pathogenesis of depression.7,8 Furthermore, other dopaminergic projections (ie, mesostriatal, mesocortical) may play a role in mediating additional symptoms of depression that appear to lie at the core of this disorder (eg, psychomotor symptoms, loss of motivation)9,10 and its melancholic subtype.11
Basic research on the brain reward and motivation systems and animal models of anhedonia and psychomotor symptoms12-15 have provided a foundation for investigating the role of dopaminergic and associated neurocircuitry in the pathogenesis of depression. Complementary work16,17 has shown that neurological lesions in this circuitry can result in anhedonia or psychomotor symptoms. Finally, neuroimaging studies9,10,18-22 of anhedonic and psychomotor symptoms in depression have contributed to delineating the neurocircuitry and neurochemistry of this disorder.
Anhedonia, for example, was positively correlated with ventromedial prefrontal cortex and negatively correlated with amygdala/ventral striatal activity in response to happy stimuli (Figure 1).19 In another study,20 trait anhedonia was positively correlated to ventromedial prefrontal cortex activity during the processing of positive information, and inversely correlated with anterior caudate volume (Figure 2). Psychomotor symptoms have also been associated with frontal and caudate abnormalities in depression,9,10,23 and fatigue may involve related regions.2,24
Molecular imaging studies8,25,26 provide partial support for the role of the dopaminergic system in mediating depression, particularly depression with psychomotor symptoms.27-29 Functional brain imaging during a dopaminergic challenge has emphasized that dopaminergic circuitry is involved in altered reward processing in anhedonia (Figure 3).30 Electroconvulsive therapy and prefrontal transcranial magnetic stimulation result in increased dopamine release,8,31 and deep brain stimulation to the reward circuitry is able to relieve anhedonia in treatment-resistant depression.32
Depression involves a range of other circuits and chemicals, and the extent to which anhedonia, psychomotor symptoms, and other features associated with reduced positive affect are specifically linked to dopaminergic dysfunction is debatable.33,34 Several other systems and molecules that play an important role in mediating depression intersect closely with the dopaminergic system; these include serotonin,35 glutamate,36 opioids,37 the hypothalamic-pituitary-adrenal axis,38 and neurotrophic factors.39,40 However, certain depressive symptoms may be more specifically linked to one of these systems.2,41
The heritability of anhedonia and psychomotor symptoms deserves further study.42,43 Response to early maternal separation and to other stressors is mediated in part by dopaminergic circuitry,15,44 and dopaminergic gene variants and their interactions with environmental stressors play a role in the pathogenesis of depression.45,46 Still, a range of other gene-environment mechanisms are also likely to play a role in this condition.47,48 Research on the relationship between dopaminergic receptor variants, cortico-striatal activation, and responsivity to reinforcers,49 may ultimately be relevant to understanding the pathogenesis of depression.
A range of evolutionary theories have been put forward to explain anhedonia and psychomotor symptoms in depression.50,51 Nesse,50 for example, notes that low mood increases ability to cope with situations in which effort to pursue a major goal will likely result in danger, loss, bodily damage, or wasted effort. Similarly, others51 have argued that depression represents an adaptive response to the perceived threat of exclusion from important social relationships. Some evolutionary theories have focused specifically on the importance of anhedonia.52
Anhedonia and psychomotor symptoms seem to be particularly core features of major depression, and also characterize its melancholic subtype.5,9,53 Other important symptoms of depression may also fall under the rubric of reduced positive affect (eg, lack of energy).33 Nevertheless, it is important to emphasize that symptoms such as anhedonia and psychomotor symptoms occur in a broad range of other medical conditions, including psychotic disorders, Parkinson’s disease, and cocaine withdrawal.
There are a number of scales of anhedonia including the Snaith-Hamilton Pleasure Scale, the Fawcett-Clark Pleasure Capacity Scale, and the Revised Chapman Physical Anhedonia Scale, and these do not completely overlap.54 The Salpêtrière retardation rating scale, the CORE Assessment of Psychomotor Change, and the Motor Agitation and Retardation Scale, are observer-rated measures to assess psychomotor abnormalities, and a range of more sensitive experimental performance measures is also available.10,55
Dopaminergic agents have a useful role to play in the treatment of depression and treatment-resistant depression.8,56,57 Both dopamine agonists and low-dose atypical antipsychotics (which increase extracellular levels of dopamine and norepinephrine, but not serotonin, in the prefrontal cortex) appear effective in the pharmacotherapy of treatment-resistant depression.2 Although effective antidepressants tend to be useful across the range of depressive symptoms, there is some evidence10,33 that dopaminergic agents are particularly useful for reduced positive affect and for psychomotor symptoms.
Depression is universally described as a “down” rather than an “up” feeling. Similarly, there is a common association between depression, anhedonia (feeling down), and psychomotor retardation (slowing down). There is growing evidence that dopaminergic mesolimbic and mesostriatal projections play an important role in mediating these symptoms. Functioning of the dopamine system is impacted on by particular gene variants as well as environmental stressors, and also by its interactions with a range of other systems. As always, researchers hope that a better understanding of these mechanisms will ultimately lead to better treatments.
1. Davidson RJ, Pizzagalli D, Nitschke JB, Putnam K. Depression: perspectives from affective neuroscience. Annu Rev Psychol. 2002;53:545-574.
2. Stahl SM, Zhang L, Damatarca C, Grady M. Brain circuits determine destiny in depression: a novel approach to the psychopharmacology of wakefulness, fatigue, and executive dysfunction in major depressive disorder. J Clin Psychiatry. 2003;64(suppl):6-17.
3. Mayberg HS, Liotti M, Brannan SK, et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999;156:675-682.
4. Klein DF. Endogenomorphic depression. A conceptual and terminological revision. Arch Gen Psychiatry. 1974;31:447-454.
5. Snaith P. Anhedonia: a neglected symptom of psychopathology. Psychol Med. 1993;23:957-966.
6. Chiu PH, Deldin PJ. Neural evidence for enhanced error detection in major depressive disorder. Am J Psychiatry. 2007;164:608-616.
7. Nestler EJ, Carlezon WA Jr. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry. 2006;59:1151-1159.
8. Nutt DJ. The role of dopamine and norepinephrine in depression and antidepressant treatment. J Clin Psychiatry. 2006;67(suppl):3-8.
9. Sobin C, Sackeim HA. Psychomotor symptoms of depression. Am J Psychiatry. 1997;154:4-17.
10. Schrijvers D, Hulstijn W, Sabbe BG. Psychomotor symptoms in depression: a diagnostic, pathophysiological and therapeutic tool. J Affect Disord. 2008;109:1-20.
11. Parker G. Classifying depression: should paradigms lost be regained? Am J Psychiatry. 2000;157:1195-1203.
12. Knutson B, Fong GW, Adams CM, Varner JL, Hommer D. Dissociation of reward anticipation and outcome with event-related fMRI. Neuroreport. 2001;12:3683-3687.
13. Bevins RA, Besheer J. Novelty reward as a measure of anhedonia. Neurosci Biobehav Rev. 2005;29:707-714.
14. Anisman H, Matheson K. Stress, depression, and anhedonia: caveats concerning animal models. Neurosci Biobehav Rev. 2005;29:525-546.
15. Willner P, Klimek V, Golembiowska K, Muscat R. Changes in mesolimbic dopamine may explain stress-induced. anhedonia. Psychobiology. 1991;19:79-84.
16. Bhatia KP, Marsden CD. The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain. 1994;117(pt 4):859-876.
17. Miller JM, Vorel SR, Tranguch AJ, et al. Anhedonia after a selective bilateral lesion of the globus pallidus. Am J Psychiatry. 2006;163:786-788.
18. Mitterschiffthaler MT, Kumari V, Malhi GS, et al. Neural response to pleasant stimuli in anhedonia: an fMRI study. Neuroreport. 2003;14:177-182.
19. Keedwell PA, Andrew C, Williams SC, Brammer MJ, Phillips ML. The neural correlates of anhedonia in major depressive disorder. Biol Psychiatry. 2005;58:843-853.
20. Harvey PO, Pruessner J, Czechowska Y, Lepage M. Individual differences in trait anhedonia: a structural and functional magnetic resonance imaging study in non-clinical subjects. Mol Psychiatry. 2007;12:703,767-775.
21. Epstein J, Pan H, Kocsis JH, et al. Lack of ventral striatal response to positive stimuli in depressed versus normal subjects. Am J Psychiatry. 2006;163:1784-1790.
22. Dunn RT, Kimbrell TA, Ketter TA, et al. Principal components of the Beck Depression Inventory and regional cerebral metabolism in unipolar and bipolar depression. Biol Psychiatry. 2002;51:387-399.
23. Videbach P. PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr Scand. 2000;101:11-20.
24. Demyttenaere K, De Fruyt J, Stahl SM. The many faces of fatigue in major depressive disorder. Int J Neuropsychopharmacol. 2005;8:93-105.
25. Klimke A, Larisch R, Janz A, Vosberg H, Müller-Gärtner HW, Gaebel W. Dopamine D2 receptor binding before and after treatment of major depression measured by [123I]IBZM SPECT. Psychiatry Res. 1999;90:91-101.
26. Nikolaus S, Antke C, Kley K, et al. Investigating the dopaminergic synapse in vivo. I. Molecular imaging studies in humans. Rev Neurosci. 2007;18:439-472.
27. Martinot MLP, Bragulat V, Artiges E, et al. Decreased presynaptic dopamine function in the left caudate of depressed patients with affective flattening and psychomotor retardation. Am J Psychiatry. 2001;158:314-316.
28. Meyer JH, McNeely HE, Sagrati S, et al. Elevated putamen D(2) receptor binding potential in major depression with motor retardation: an [11C]raclopride positron emission tomography study. Am J Psychiatry. 2006;163:1594-1602.
29. Narita H, Odawara T, Iseki E, Kosaka K, Hirayasu Y. Psychomotor retardation correlates with frontal hypoperfusion and the Modified Stroop Test in patients under 60-years-old with major depression. Psychiatry Clin Neurosci. 2004;58:389-395.
30. Tremblay LK, Naranjo CA, Graham SJ, et al. Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. Arch Gen Psychiatry. 2005;62:1228-1236.
31. Pogarell O, Koch W, Pöpperl G, et al. Acute prefrontal rTMS increases striatal dopamine to a similar degree as D-amphetamine. Psychiatry Res. 2007;156:251-255.
32. Schlaepfer TE, Cohen MX, Frick C, et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology. 2008;33:368-377.
33. Nutt D, Demyttenaere K, Janka Z, et al. The other face of depression, reduced positive affect: the role of catecholamines in causation and cure. J Psychopharmacol. 2007;21:461-471.
34. Salamone JD, Cousins MS, Snyder BJ. Behavioral functions of nucleus accumbens dopamine: empirical and conceptual problems with the anhedonia hypothesis. Neurosci Biobehav Rev. 1997;21:341-359.
35. Dremencov E, Gispan-Herman I, Rosenstein M, et al. The serotonin-dopamine interaction is critical for fast-onset action of antidepressant treatment: in vivo studies in an animal model of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:141-147.
36. Del Arco A, Mora F. Prefrontal cortex-nucleus accumbens interaction: in vivo modulation by dopamine and glutamate in the prefrontal cortex. Pharmacol Biochem Behav. 2008;90:226-235.
37. Leknes S, Tracey I. A common neurobiology for pain and pleasure. Nat Rev Neurosci. 2008;9:314-320.
38. Koob G, Kreek MJ. Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry. 2007;164:1149-1159.
39. Eisch AJ, Bolaños CA, de Wit J, et al. Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression. Biol Psychiatry. 2003;54:994-1005.
40. Slevin JT, Gash DM, Smith CD, et al. Unilateral intraputamenal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year of treatment and 1 year of withdrawal. J Neurosurg. 2007;106:614-620.
41. Meyer JH, McMain S, Kennedy SH, et al. Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm. Am J Psychiatry. 2003;160:90-99.
42. Bogan R, Pizzagalli DA. The heritability of hedonic capacity and perceived stress: a twin study evaluation of candidate depressive phenotypes. Psychol Med. In press.
43. Hasler G, Drevets WC, Manji HK, Charney DS. Discovering endophenotypes for major depression. Neuropsychopharmacology. 2004;29:1765-1781.
44. Panksepp J. Affective Neuroscience: The Foundations of Human and Animal Emotions. New York, NY: Oxford University Press; 1998.
45. Haeffel GJ, Getchell M, Koposov RA, et al. Association between polymorphisms in the dopamine transporter gene and depression: evidence for a gene-environment interaction in a sample of juvenile detainees. Psychol Sci. 2008;19:62-69.
46. Elovainio M, Jokela M, Kivimäki M, et al. Genetic variants in the DRD2 gene moderate the relationship between stressful life events and depressive symptoms in adults: cardiovascular risk in young Finns study. Psychosom Med. 2007;69:391-395.
47. Uher R, McGuffin P. The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis. Mol Psychiatry. 2008;13:131-146.
48. Brown GW, Harris TO. Depression and the serotonin transporter 5-HTTLPR polymorphism: a review and a hypothesis concerning gene-environment interaction. J Affect Disord. 2008 Jun 3. [Epub ahead of print].
49. Klein TA, Neumann J, Reuter M, Hennig J, von Cramon DY, Ullsperger M. Genetically determined differences in learning from errors. Science. 2007;318:1642-1645.
50. Nesse RM. Is depression an adaptation? Arch Gen Psychiatry. 2000;57:14-20.
51. Allen NB, Badcock PB. Darwinian models of depression: a review of evolutionary accounts of mood and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:815-826.
52. De La Garza R 2nd. Endotoxin- or pro-inflammatory cytokine-induced sickness behavior as an animal model of depression: focus on anhedonia. Neurosci Biobehav Rev. 2005;29:761-770.
53. Taylor MA, Fink M. Restoring melancholia in the classification of mood disorders. J Affect Disord. 2008;105:1-14.
54. Leventhal AM, Chasson GS, Tapia E, Miller EK, Pettit JW. Measuring hedonic capacity in depression: a psychometric analysis of three anhedonia scales. Journal Of Clinical Psychology. 2006;62:1545-1558.
55. Sobin C, Mayer L, Endicott J. The motor agitation and retardation scale: a scale for the assessment of motor abnormalities in depressed patients. J Neuropsychiatry Clin Neurosci. 1998;10:85-92.
56. Zimmerman M, Posternak MA, Attiullah N, et al. Why isn’t bupropion the most frequently prescribed antidepressant? J Clin Psychiatry. 2005;66:603-610.
57. Dailly E, Chenu F, Renard CE, Bourin M. Dopamine, depression and antidepressants. Fundamental & Clinical Pharmacology. 2004;18:601-607.