7. Dopamine and Depression

These commentaries are based on Dr Gillman’s peer reviewed scientific papers, see Publications

Introduction: Importance of Dopamine in Depression

Readers may appreciate that I have always thought and taught that the role of dopamine (DA) in depression has been neglected and under-appreciated.  There is no doubt that it plays a vital role in motivation, anhedonia, and cognition, which are central changes to the debilitating effects of the illness and are inadequately addressed by almost all other antidepressants. 

Undeniably, there are no other generally accepted effective antidepressants which elevate all relevant neurotransmitters, including dopamine, except MAOIs.

That is precisely why, from the earliest phase of my career, I have always used MAOIs for the treatment of people with more severe depression.  MAOIs are the main drugs that actually increase dopamine levels (or at least they were the main such drugs available for use in humans for most of the time I was in practice).

Not long after my wife and I married, just before we came to Australia in 1983, I asked her to make sure that, if I ever failed to laugh at ‘Yes, Prime Minister’, she was to have me put on tranylcypromine immediately.

More severe illnesses are characterised by greater degrees of reduction in motivation (anergia), anhedonia (pleasure), and cognition; in severe retarded depression the patient’s state may reach one approaching stupor.

It is a salutary lesson, and surprising, to learn (or remember) that anhedonia was not included as a core symptom of depression until ICD-10, in 1992 and DSM-IV, in 1994.  I confess I did not appreciate that until I did the research for this commentary and it astonished me — if that is reflected in the general teaching of specialists, and in the average clinician’s conception of depressive illness, no wonder it is treated within insufficient regard for dopaminergic strategies.

It is my firm opinion that moderate-to-severe degrees of illness do not recover completely without the assistance of a dopamine increasing treatment strategy.

Recent reviews

Reviewing the research for this commentary reminded me there have been some noteworthy reviews relating to dopamine in depression, including one by my old associate, professor David Nutt [1], and Dunlop [2], who I am pleased to note cites van Praag; he observed there was:

A convergence of data from animal models, genetics, neuroimaging, and human clinical trials. …

However, most antidepressant treatments do not directly enhance DA neurotransmission, which may contribute to residual symptoms, including impaired motivation, concentration, and pleasure.

Dunlop seems to have nailed it some 10 years ago, I completely agree with his statement above.

As the professor of translational psychopharmacology at UCL, Professor Clare Stanford, has more recently stated [3] ‘dopaminergic transmission makes an essential contribution to promoting motivation and cognition, as well as preventing anhedonia’.

I also note that — better late than never — the importance of dopamine and anhedonia are creating more research interest.  The listed reviews attest to an increasing number of papers on the subject that have come out since I last reviewed this field of endeavour.

I find it striking that Argyropoulos & Nutt [1] offer as the explanation (for the neglect of dopamine-in-depression research):

‘the success of the TCAs and the SSRIs/ SNRIs in treating the condition made the researchers into its aetiology concentrate mainly on these latter two transmitters.’

But, manifestly, they [TCAs and the SSRIs/ SNRIs] were not successful, except in a proportion of patients — hence the current preoccupation with so-called TRD, so that seems to be a rather imprecise post hoc rationalisation.

It is also notable that various of these reviewers make statements such as that by Treadway ‘Anhedonia has long been recognized as a central feature of major depression’.  People from different backgrounds will have varying perceptions of what has, or has not, been generally recognised, and by whom.  From my standpoint, as a widely read clinical researcher, it seems clear to me that under-recognition of anhedonia and DA has been the dominant zeitgeist — Serotee has had a full dance-card and Dopar has languished in the scullery [you will understand that allusion when you have read ‘Cinderella — a children’s fairy tale’, below].

This reflects the degree of communication between experienced clinicians and those doing research; I would say to such researchers that it is quite clear that drugs that also affect dopamine are manifestly superior for the treatment of more severe melancholic depression.  It is arguable that misunderstanding and misinterpretation of what really works in clinical practice has played a significant part in misleading and misdirecting basic researchers.

Major or significant reviews consulted or referred to in this commentary are: 

Anhedonia revisited: is there a role for dopamine-targeting drugs for depression? [1]

Psychostimulants, antidepressants and neurokinin-1 receptor antagonists (‘motor disinhibitors’) have overlapping, but distinct, effects on monoamine transmission: the involvement of L-type Ca2+ channels and implications for the treatment of ADHD [3]

Reconceptualizing anhedonia: novel perspectives on balancing the pleasure networks in the human brain [4]

The Neurobiology of Motivational Deficits in Depression — An Update on Candidate Patho-mechanisms [5]

Dopamine System Dysregulation in Major Depressive Disorders [6]

Dopamine, Effort-Based Choice, and Behavioral Economics: Basic and Translational Research [7]

Neuroscience of apathy and anhedonia: a transdiagnostic approach [8]

Anhedonia in depression and schizophrenia: A transdiagnostic challenge [9]

Neurobiological Reward-Related Abnormalities Across Mood Disorders [10]

Pharmacological interventions targeting anhedonia in patients with major depressive disorder: A systematic review [11]

As one can see from these titles a broader view of anhedonia is now being taken and I am sure van Praag would be pleased.  It is notable that Cao’s review does not even mention MAOIs at all, but only mentions drugs like bupropion, which is only weakly dopaminergic — doubtless, to some extent at least, that reflects the research that has been done, or, more to the point, not been done.

Consequently, I have finally got around to writing a commentary specifically focused on DA and motivation, anhedonia, and cognition.  This is intended to help readers understand why I have always espoused much greater use of MAOIs — they remain the best way of achieving the objective of elevating DA neuronal activity (whilst also boosting NA and 5-HT).  

No other drug available for use in humans elevates all of those neurotransmitters.

I have said this in another commentary — when I taught in London, I used to say that amitriptyline (just an NRI) was petrol, clomipramine (a real ‘SNRI’) was aviation fuel, but TCP was rocket fuel (in fact, the hydrazine MAOIs literally are rocket fuel).  Indeed, I was responsible for the last advertisement for Parnate published in the UK which, at my suggestion, showed a picture of the space shuttle launch (to replace the picture of the ageing Wessex air-sea rescue helicopter, lifting somebody out of the sea, with the caption ‘Parnate for the powerful lift’).

Cinderella — a children’s fairy tale

Now then children, are you tucked-in comfortably, Uncle Ken will read you a bed-time story — Once upon a time a little orphan molecule called Dopar was adopted by a wicked uncle called Big P. Harmer: he was fat and greedy, and his wife was mean and she told lots of whopping fibs (you might think, children, she was a bit like that ginger-haired man you keep seeing on television, and he tells more bigger fibs than anyone in the whole wide world, as even children know).

Horrid Harmer and his wife had two children of their own, Serotee and Nora — they were selfish and lazy children and did little work around the house; they rarely helped anyone much at all.  Serotee and Nora were mollycoddled and spoilt, and they spent a lot of money on them.  They sent them to lots of beauty pageants and brought them heaps of expensive dresses, especially Serotee, who was pretty, popular, and fashionable.  They were very, very rich, so they paid for all her friends (who they gave the secret name of KOLs) to go along to the beauty pageants and cheer for her, and say ‘yes, yes, yes’ to all her silly ideas (well children, they weren’t really friends, but they liked the candyfloss, the money and the trips, which made them feel important).  This made it look as though she was more popular than she really was.

Poor little Dopar was confined to the house doing menial jobs and never allowed out.  She was neglected and ignored, even though she did some really good things for the few people she sometimes met.  Then one day…

Now children, it’s time to put the candles out and go to sleep, but if you’re good, I’ll read you the rest of the story another day.

Is the fairy godmother close at hand?

Perhaps Dopar’s fairy godmother is approaching in her golden carriage.  Maybe Dopar is finally going to get a ‘makeover’ and marry the prince.

Dopamine-depleting drugs and illnesses

DA matters

This commentary details the clear indications demonstrating that we should be treating ‘melancholic’ depression by increasing dopamine; definitely not decreasing with ‘anti-psychotic’ drugs (DA antagonists) — which makes about as much sense as bleeding people to treat anaemia: and we gave up doing that a couple of hundred years ago.

The mesolimbic dopamine (DA) system is intimately involved in regulating effort-related aspects of motivation and reward, as discussed in detail in a recent review [7]. 

Mental energy, motivation and cognition are all linked and patients with major depression show greater memory improvement if motivation is increased [12, 13].  Patients on neuroleptic drugs sometimes describe the feeling that they are ‘thinking in cold porridge’.  An essential phenomenon in Parkinson’s disease is not only bradykinesia, but also bradyphrenia, that is slow movement and slow thinking.

In animals, even low doses of DA antagonists — like quetiapine or other antipsychotics, and likewise DA depleting-drugs, like reserpine and tetrabenazine (TBZ), mimic aspects of the depressive syndrome: they impair energy and reward-related behaviours.  Across multiple paradigms, even low doses of DA antagonists and DA depleting-drugs reduce the tendency to work for high reward options and increase selection of low reward choices [14-20].

In animal models DRIs, including even the rather weak DRI Bupropion (BUP), attenuate such impairment, whereas inhibitors of NAT and SERT have no effect; of note SRIs can make it worse [21-26].

The MAO-B inhibitor selegiline induces partial reversal of the effort-related motivational effects of TBZ [27].

These results from animal studies are consistent with the reported human clinical data in a highly-cited paper by Treadway et al. showing that patients with major depression show reduced selection of high effort alternatives in tests of effort-based decision making [28].

Parkinson’s disease, Dopamine, depression

The incidence of major depression, using usual research methodology, in community samples of patients with Parkinson disease (in which dopamine deficiency plays a major role, although other neurotransmitters are also reduced) is 5% to 10% with an additional 10% to 30% experiencing subsyndromal depressive symptoms: that has been posited for a long time, and is further attested to by more recent research [29-33].

The true incidence is probably higher because researchers have used insufficiently sensitive instruments to measure the dimensions of anhedonia and anergia.

In humans, drugs that lower dopamine (most commonly the neuroleptic drugs) lead to Parkinsonian and depressive-like symptoms, as well as causing or worsening parkinsonian movement disorder.  Tetrabenazine (TBZ), which has been around for decades, and reserpine, both induce depressive-like symptoms and ‘fatigue’ in humans [34-37].

In his comprehensive review ‘The myth of reserpine-induced depression’ Baumeister [38] notes that the evidence for precipitating typical depressive syndromes is poor, but that the evidence for the induction of ‘psychomotor retardation, agitation and lassitude’ is rather better.  A more recent detailed assessment of this entitled; ‘Evaluating depression and suicidality in tetrabenazine users with Huntington disease’ [39] seems to suggest that depression (as traditionally diagnosed and defined, by less-than-perfect rating scales) and suicidality, are not increased — there has been some debate about the methodology of that study; nevertheless, if tetrabenazine precipitated major depression as a true causal mechanism, that surely would have been obvious with such a large number of patients in the database (Enroll-HD database has nearly 9,000 cases), quibbles about methodology notwithstanding.

Administration of alpha-methylparatyrosine, an inhibitor of tyrosine hydroxylase, reduces levels of catecholamines and in one trial increased depressive symptoms, particularly anhedonia, poor concentration, and loss of energy, in patients who had previously achieved remission of their depression [40].

Likewise, note that with serotonin tryptophan depletion in healthy subjects does not produce clinically significant changes in mood; however, recovered depressed patients free of medication can show brief, clinically relevant, depressive symptomatology [41].

Such results highlight the key point of understanding that depressive illnesses may be better conceptualised as a spectrum of signs and symptoms in several component dimensions that are probably related to particular neurotransmitters (e.g. dopamine and motivation, but lack of motivation alone does not depression make).  Some of the references given herein discuss subtleties relating to anticipatory versus consummatory anhedonia and such issues, but these are beyond the scope of this commentary — indeed, it is arguable that they do not matter from the point of view of the clinical problem of making patients with serious depression better, providing they are getting good improvement in their motivation and concomitant reduction in the feeling of anergia and anhedonia, however that might be defined or dissected.  There is enough clear evidence that dopamine is crucial to all of this for us to suppose that elevating dopamine is essential.

The above illustrates that the catchall term of ‘depression’ is a blunt instrument with which to dissect meaning in such studies.

A dimensional interpretation of the role of neurotransmitters in the genesis of the various dimensions of the depressive syndrome indicates clearly that the above findings are what we would expect, and it fit with other evidence — I have cited Herman van Praag’s papers from nearly 50 years ago multiple times, Van Praag seems to have been forgotten [42, 43], except by Dunlop.

Dopamine antagonists

DA antagonists (neuroleptics), such as quetiapine, reduce signals in dopamine pathways.  That strongly indicates it is ill-advised to use them to attempt to augment treatment response in serious melancholic-type depressions.  Theory, and animal data, predict that action is the exact opposite of the increase in DA that strong evidence indicates is required.

The clinical evidence that quetiapine augmentation actually has any substantive benefits is weak — a couple of points on a rating scale does not an anti-depressant make — in my submission any minor benefits are quite insufficient to justify administration of a class of drugs with so many long-term side-effects.  Any self-respecting Bayesian would want much stronger evidence of more substantial benefit.

DA antagonists such as quetiapine most certainly do not improve drive, motivation and energy — and that is what patients with severe depression need improved.


There is now a very substantial amount of evidence [in my opinion, it is overwhelming evidence] pointing to the fact that the neurotransmitters noradrenaline, serotonin, and dopamine are all involved in one way or another in the syndrome of serious anergic, anhedonic, melancholic-type depression, and that increasing all of them tends to produce greater benefit, and increasing dopamine is essential to obtain full remission.

If a patient has serious depression, with function-impairing anergia and anhedonia, and especially if they have decreasing levels of neurotransmitters with advancing age (i.e. >60 years), whether or not they have parkinsonian symptoms, or cognition difficulties, one would have to take the view that it is irrefutably logical to make an MAOI like tranylcypromine a highly favoured antidepressant choice.

It is what I would advise to my nearest and dearest, and as I said above, my wife has strict instructions about what to do if I stop laughing at ‘Yes, Prime Minister’.

Part two of this commentary will look in more detail at the drugs that are available to use, singly, or in combination, in treatment strategies aimed at increasing dopamine levels.



1. Argyropoulos, S.V. and D.J. Nutt, Anhedonia revisited: is there a role for dopamine-targeting drugs for depression? J Psychopharmacol, 2013. 27(10): p. 869-77.

2. Dunlop, B.W. and C.B. Nemeroff, The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry, 2007. 64(3): p. 327-37.

3. Stanford, S.C., Psychostimulants, antidepressants and neurokinin-1 receptor antagonists (‘motor disinhibitors’) have overlapping, but distinct, effects on monoamine transmission: the involvement of L-type Ca2+ channels and implications for the treatment of ADHD. Neuropharmacology, 2014. 87: p. 9-18.

4. Romer Thomsen, K., P.C. Whybrow, and M.L. Kringelbach, Reconceptualizing anhedonia: novel perspectives on balancing the pleasure networks in the human brain. Front Behav Neurosci, 2015. 9: p. 49.

5. Treadway, M.T., The Neurobiology of Motivational Deficits in Depression–An Update on Candidate Pathomechanisms. Curr Top Behav Neurosci, 2016. 27: p. 337-55.

6. Belujon, P. and A.A. Grace, Dopamine System Dysregulation in Major Depressive Disorders. Int J Neuropsychopharmacol, 2017. 20(12): p. 1036-1046.

7. Salamone, J.D., et al., Dopamine, Effort-Based Choice, and Behavioral Economics: Basic and Translational Research. Frontiers in behavioral neuroscience, 2018. 12: p. 52-52.

8. Husain, M. and J.P. Roiser, Neuroscience of apathy and anhedonia: a transdiagnostic approach. Nature Reviews Neuroscience, 2018. 19(8): p. 470-484.

9. Lambert, C., et al., Anhedonia in depression and schizophrenia: A transdiagnostic challenge. CNS Neurosci Ther, 2018. 24(7): p. 615-623.

10. Whitton, A.E., et al., Neurobiological Reward-Related Abnormalities Across Mood Disorders. The Oxford Handbook of Positive Emotion and Psychopathology, 2019: p. 223.

11. Cao, B., et al., Pharmacological interventions targeting anhedonia in patients with major depressive disorder: A systematic review. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2019.

12. Rutherford, B.R., et al., Effects of L-DOPA Monotherapy on Psychomotor Speed and [11C] Raclopride Binding in High-Risk Older Adults With Depression. Biological psychiatry, 2019. 86(3): p. 221-229.

13. Dehn, L.B., M. Driessen, and T. Beblo, Patients with major depression show greater memory improvement if motivation is increased: An exploratory study under real-life-like conditions. Journal of Clinical and Experimental Neuropsychology, 2020: p. 1-12.

14. Salamone, J.D. and M. Correa, The mysterious motivational functions of mesolimbic dopamine. Neuron, 2012. 76(3): p. 470-85.

15. Salamone, J.D., et al., Mesolimbic Dopamine and the Regulation of Motivated Behavior. Curr Top Behav Neurosci, 2016. 27: p. 231-57.

16. Salamone, J.D., et al., The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation. Pharmacol Rev, 2018. 70(4): p. 747-762.

17. Floresco, S.B., M.T. Tse, and S. Ghods-Sharifi, Dopaminergic and glutamatergic regulation of effort- and delay-based decision making. Neuropsychopharmacology, 2008. 33(8): p. 1966-79.

18. Randall, P.A., et al., Dopaminergic modulation of effort-related choice behavior as assessed by a progressive ratio chow feeding choice task: pharmacological studies and the role of individual differences. PLoS One, 2012. 7(10): p. e47934.

19. Hosking, J.G., S.B. Floresco, and C.A. Winstanley, Dopamine antagonism decreases willingness to expend physical, but not cognitive, effort: a comparison of two rodent cost/benefit decision-making tasks. Neuropsychopharmacology, 2015. 40(4): p. 1005-15.

20. Mai, B., S. Sommer, and W. Hauber, Motivational states influence effort-based decision making in rats: the role of dopamine in the nucleus accumbens. Cogn Affect Behav Neurosci, 2012. 12(1): p. 74-84.

21. Yohn, S.E., et al., Not All Antidepressants Are Created Equal: Differential Effects of Monoamine Uptake Inhibitors on Effort-Related Choice Behavior. Neuropsychopharmacology, 2016. 41(3): p. 686-94.

22. Yohn, S.E., et al., Blockade of uptake for dopamine, but not norepinephrine or 5-HT, increases selection of high effort instrumental activity: Implications for treatment of effort-related motivational symptoms in psychopathology. Neuropharmacology, 2016. 109: p. 270-80.

23. Yohn, S.E., et al., Evaluation of the effort-related motivational effects of the novel dopamine uptake inhibitor PRX-14040. Pharmacol Biochem Behav, 2016. 148: p. 84-91.

24. Yohn, S.E., et al., The monoamine-oxidase B inhibitor deprenyl increases selection of high-effort activity in rats tested on a progressive ratio/chow feeding choice procedure: Implications for treating motivational dysfunctions. Behavioural brain research, 2018. 342: p. 27-34.

25. Randall, P.A., et al., The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs. PloS one, 2014. 9(6): p. e99320-e99320.

26. Randall, P.A., et al., Bupropion increases selection of high effort activity in rats tested on a progressive ratio/chow feeding choice procedure: implications for treatment of effort-related motivational symptoms. International Journal of Neuropsychopharmacology, 2015: p. pyu017.

27. Contreras-Mora, H., et al., Partial reversal of the effort-related motivational effects of tetrabenazine with the MAO-B inhibitor deprenyl (selegiline): Implications for treating motivational dysfunctions. Pharmacology, biochemistry, and behavior, 2018. 166: p. 13-20.

28. Treadway, M.T., et al., Effort-based decision-making in major depressive disorder: a translational model of motivational anhedonia. J Abnorm Psychol, 2012. 121(3): p. 553-8.

29. Cummings, J.L. and D.L. Masterman, Depression in patients with Parkinson’s disease. Int J Geriatr Psychiatry, 1999. 14(9): p. 711-8.

30. Heinzel, S., et al., Do We Need to Rethink the Epidemiology and Healthcare Utilization of Parkinson’s Disease in Germany? Front Neurol, 2018. 9: p. 500.

31. Larsen, J.P., et al., The natural history of depressive symptoms in patients with incident Parkinson’s disease: a prospective cohort study. J Neurol, 2017. 264(12): p. 2401-2408.

32. Hsu, Y.T., et al., Increased Risk of Depression in Patients with Parkinson Disease: A Nationwide Cohort Study. Am J Geriatr Psychiatry, 2015. 23(9): p. 934-40.

33. Wu, Y.H., et al., Depression in Parkinson’s disease: A case-control study. PLoS One, 2018. 13(2): p. e0192050.

34. Frank, S., Tetrabenazine: the first approved drug for the treatment of chorea in US patients with Huntington disease. Neuropsychiatr Dis Treat, 2010. 6: p. 657-65.

35. Jankovic, J. and J. Orman, Tetrabenazine therapy of dystonia, chorea, tics, and other dyskinesias. Neurology, 1988. 38(3): p. 391-4.

36. Kenney, C., et al., Is history of depression a contraindication to treatment with tetrabenazine? Clin Neuropharmacol, 2006. 29(5): p. 259-64.

37. Kenney, C., C. Hunter, and J. Jankovic, Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders. Movement Disorders, 2007. 22(2): p. 193-7.

38. Baumeister, A.A., M.F. Hawkins, and S.M. Uzelac, The myth of reserpine-induced depression: role in the historical development of the monoamine hypothesis. J Hist Neurosci, 2003. 12(2): p. 207-20.

39. Schultz, J.L., et al., Evaluating depression and suicidality in tetrabenazine users with Huntington disease. Neurology, 2018. 91(3): p. e202-e207.

40. Miller, H.L., et al., Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry, 1996. 53(2): p. 117-28.

41. Smith, K.A., C.G. Fairburn, and P.J. Cowen, Relapse of depression after rapid depletion of tryptophan. Lancet, 1997. 349(9056): p. 915-9.

42. van Praag, H., et al., Monoamines and Abnormal Behaviour.  A Multi-Aminergic Perspective. British Journal of Psychiatry, 1990. 157: p. 723-734.

43. van Praag, H.M., Nosologomania: a disorder of psychiatry. World J Biol Psychiatry, 2000. 1(3): p. 151-8.


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