Stimulants have been intuitively considered as treatment options for depression for a very long time. It is often said that Freud treated his own depression by snorting cocaine.
Methylphenidate (Ritalin) was first systematically studied in the treatment of depression in the UK in 1958 by Robin & Wiseberg, with spectacularly negative results. But the allure of the rapid action and the broad monoaminergic effects of stimulants meant that we clinicians never lost our interest in this class of drugs for treating depression! In many cases of treatment resistance as well as in psycho-oncology practice, stimulants are used for depressive symptoms.
To date, there have been 2 RCTs on methylphenidate, 2 on modafinil, 3 on lisdexamfetamine (Vyvanse) as augmentation agents to antidepressants (predominantly SSRIs or venlafaxine) but none of them have demonstrated a convincing clinical or statistical advantage for efficacy (1).
Nevertheless, for specific forms of depression, such as bipolar depression, there is some support for psychostimulant augmentation ( 1 RCT on modafinil; 4 RCTs on armodafinil). I say ‘some’ support, as 16 patients with bipolar depression need to be augmented with modafinil for one additional subject to achieve remission. But it is worth noting that you are 4 times more likely to help than harm a patient with bipolar depression when trying this adjunct treatment (The likelihood to be helped or harmed (LHH = NNH/NNT = 4.26) (2).
Various speculations exist to explain the spectacular lack of supportive evidence for psychostimulants in depression.
- Stimulants may only benefit a subgroup of depressed patients with excess sleepiness and lack of drive (i.e., atypical depression) (3).
- For a given patient, some [i.e. neurocognitive (executive dysfunction) and neurovegetative (melancholic)] but not all features of depression may respond better (4).
So what do we need to know when considering the use of stimulants for depression in practice?
- Evidence to use stimulants as monotherapy or adjuvants for MDD is weak, not supportive of routine consideration. Ritalin, Vyvanse and Modafinil have been studied in this regard.
- For bipolar depression, modafinil has more encouraging evidence base (armodafinil at 150mg/day or modafinil at 200mg/day) as adjuvant to various combinations of mood stabilisers
- If you are planning to use stimulants in MDD or bipolar depression, please remember that (1) combining stimulants with TCAs or MAOIs can increase the risk of hypertensive crisis as well as serotonin syndrome (2) most controlled trials have been short-term studies (~8 weeks), so there is not much leg to stand on when using stimulants for long periods when a response is not forthcoming.
- It is important to keep in mind the habit forming potential of stimulants. “If there is one person who can be held responsible for the emergence of cocaine as a recreational pharmaceutical, it was Freud.” – Dominic Streatfeild, in the book “Cocaine: An Unauthorized Biography”
References
- Faraone SV. The pharmacology of amphetamine and methylphenidate: relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neuroscience & Biobehavioral Reviews. 2018 Apr 1;87:255-70.
- Nunez NA, Singh B, Romo‐Nava F, Joseph B, Veldic M, Cuellar‐Barboza A, Cabello Arreola A, Vande Voort JL, Croarkin P, Moore KM, Biernacka J. Efficacy and tolerability of adjunctive modafinil/armodafinil in bipolar depression: A meta‐analysis of randomized controlled trials. Bipolar disorders. 2020 Mar;22(2):109-20.
- Hegerl U, Hensch T. Why do stimulants not work in typical depression?. Australian & New Zealand Journal of Psychiatry. 2017 Jan;51(1):20-2.
- McIntyre RS, Lee Y, Zhou AJ, Rosenblat JD, Peters EM, Lam RW, Kennedy SH, Rong C, Jerrell JM. The efficacy of psychostimulants in major depressive episodes: a systematic review and meta-analysis. Journal of Clinical Psychopharmacology. 2017 Aug 1;37(4):412-8.