Psychotic depression and tranylcypromine
For decades now I have been puzzled by the readiness of psychiatrists to give anti-dopaminergic, so called ‘antipsychotic’ drugs, to patients with severe depression, especially those designated as having ‘psychotic’ depression. The evidence that this strategy is effective is poor. My experience of using tranylcypromine (Parnate) in many such cases indicates clearly it is a much superior strategy with far less side-effects. There are some differences in treatment response that are so clear that you do not need a double-blind trial to demonstrate them (think penicillin, and, have a laugh, parachutes (1)).
Incidentally, as Smith et al. (1) humorously remind us, doctors and psychiatrists who think that the only acceptable evidence is a double-blind trial need to think again: that is erroneous. The very fact that it is easy to find a series of trials which go in a logically inconsistent circle, by proving drug A is superior to drug B, drug B to C, and then C to A, is eloquent testimony to the fact that many such trials are actually flawed.
That is why I am now re-publishing my contribution (below) to a paper that appeared in the British Journal of Psychiatry in 2006 (2), because I felt it was important to document my experience, and now, to ensure it remains ‘on the record’ (since the BJP have, rudely, ‘unpublished’ it recently without informing me). As I was preparing to post the personal narrative, from a man who consulted me via the website (a TCP responder who had failed to benefit from several courses of ECT), link,
I went to check the availability of this previous publication. Since I thus discovered that it is no longer available on the BJP site, I decided to re-publish it on my own website in its original form but with this brief introduction.
Let me explain why it is that I have for so long been puzzled by the readiness of psychiatrists to give anti-dopaminergic ‘antipsychotic’ drugs to patients with severe depression.
A considerable amount of evidence, over the last 50 years, points to the fact that depression is to do with under-activity in the brain (brady-phrenia and brady-kinesia) and under-activity of various neurotransmitters, certainly including dopamine. Dopamine undoubtedly has a major role in motivation and pleasure, both of which are absolutely central to severe depression, as reprised recently in papers picking up this theme (3-5). Why on earth, you might well ask, would somebody think that further reducing dopamine with ‘antipsychotics’ was a good idea? Bayesian reasoning would suggest that the evidence for that proposition would have to be overwhelming before it would be logical to consider it seriously, never mind act on it. However, the clinical evidence that antipsychotics are beneficial in severe depression is very poor indeed: it should not be accepted or acted upon, especially because such drugs have major problems and side effects (6).
I suspect the explanation for the extensive use of antipsychotics in depression (aside from promotion by drug companies) is, in large part, rather simple and a little embarrassing. Labels tend to be used rather carelessly and words like ‘psychotic’ are often defined and used imprecisely. The psychosis of schizophrenia and the so-called psychosis of depression are as different as chalk and cheese. The simplistic idea that drugs that are often referred to as antipsychotics and used for schizophrenia must therefore be effective in an illness called ‘psychotic’ depression is naïve, baseless and ridiculous.
I regard the administration of antipsychotics to treat depression as one of the stupidest and most shameful exercises engaged in by psychiatrists. They are the most horribly overused and misused drugs.
Thus it would appear that a misconceived semantic association has influenced thinking and practice in the absence of any pharmacological justification or firm evidence: that is not good science.
Lastly, I wish to emphasise that apart from this publication below I have seen and treated many patients with severe agitated and psychotic depression with tranylcypromine, with great success. I have seen many patients over the years who have failed to respond to ECT, or relapsed soon after having had it, who have remitted and stayed well on tranylcypromine — which is the only anti-depressant we have that substantially elevates dopamine. To this day I remain puzzled that no-one in the ‘current era’ has ‘trialled’ TCP for psychotic depression.
It was in actual fact ‘trialled’ for psychotic depression, although not to standards that would be generally regarded as satisfactory now. Most people have forgotten that tranylcypromine was accepted as being very effective the psychotic depression, before it was temporarily removed from the American market in 1964 as a result of the hysteria about the ‘cheese reaction’. You can read about how the FDA ‘DESI’ initiative flexed its muscles at that time by only allowing TCP back on the market for atypical depression, and stating specifically that it was contra-indicated for psychotic and melancholic depression: that quite extra-ordinary story of DESI is contained in another of my commentaries –
‘Psychotic depression and ‘multi-aminergic’ treatment strategies’
P K Gillman
Originally published in British Journal of Psychiatry (in response to Wijkstra, J., Lijmer, J., Balk, F. J., et al (2006) ‘Pharmacological treatment for unipolar psychotic depression: Systematic review and meta-analysis’. e-letter.
To the Editor,
The resurgence of the suggestion that neuroleptic drugs should be used for treatment of psychotic, or refractory, depression is important because of the potential for worsening the illness; i.e. by lowering dopamine when it may need to be raised. A previous meta-analytic study (Parker, Roy, et al, 1992) found a significant effect size only for the superiority of ECT over TCAs, but not TCAs + neuroleptic over TCAs, or MAOIs. The Wijkstra et. al. study (2006) substantiates the case against the usefulness of neuroleptics in psychotic depression. However, neither study was able to distinguish between 5-HT and NA (SNRI), vs. mono-aminergic, treatment strategies. It is both curious and disappointing that more attempts have not been made to simultaneously augment multiple mono-amine pathways, for two reasons: 1) major depression probably involves changes in NA, 5HT and DA. 2) the SNRI clomipramine is of superior efficacy for severe depression (DUAG, 1986).
Any results which suggest the superiority of SNRI over mono- aminergic strategies, like standard TCAs (which increase NA, but affect 5HT and DA very little, except for clomipramine), are thus of considerable importance. See Gillman (2006) for an in depth analysis of the issue of which TCAs exhibit clinically relevant SNRI potency.
I therefore report my analysis of 21 consecutive cases of psychotic depression, treated using SNRI strategies. Nineteen of the 21 (90%) recovered fully without either neuroleptics or ECT. Only unequivocal clinical data indicating delusions were used to justify the diagnosis of psychotic depression. All patients were adjudged to be fully recovered by virtue of the fact that they were able to leave hospital and resume their normal functioning and responsibilities without significant functional impairment or symptoms. All were treated, and all followed up for a minimum of 2 years, by the author and remained well: except those few patients who did not maintain the same maximal dose throughout follow-up. All those showed signs of early relapse, but recovered on restitution of the maximal dose.
Ten (of 21) cases had had no previous treatment in the index episode. Two had received bilateral ECT in the index episode prior to referral ; 2 had bilateral ECT given by the author. Of the total of 21, 15 received clomipramine alone, 3 tranylcypromine alone, 2 sertraline + nortriptyline, 1 ECT (recovered). Three of the 4 ECT cases relapsed rapidly, but all 3 remitted with drug treatment.
Prudic’s (1990) results showed that about 85% of psychotic depressives respond to ECT, but 60% relapse within 1 year: leading them to sum up: ‘The implication is that 20% of medication resistant patients respond (to ECT) and maintain gains for 1 year’. So, as Wijkstra et. al. note, the fact that ‘many clinicians assume that ECT is more effective than pharmacotherapy’ is especially unfortunate. I hope my experience will encourage others to try ‘multi-aminergic’ strategies including MAOIs and sertraline + nortriptyline.
Danish University Antidepressant Group (1986) Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Danish University Antidepressant Group. Psychopharmacology, 90, 131-138.
Gillman, P. K. (2006) A Review of Serotonin Toxicity Data: Implications for the Mechanisms of Antidepressant Drug Action. Biological Psychiatry, [Feb 3; Epub ahead of print].
Parker, G., Roy, K., Hadzi-Pavlovic, D., et al (1992) Psychotic (delusional) Depression: a meta-analysis of Physical Treatments. Journal of Affective Disorders, 24, 17 -24.
Prudic, J., Sackeim, H. A. & Devanand, D. P. (1990) Medication Resistance & Clinical response to Electroconvulsive Therapy. Psychiatry Research, 31, 287 -296.
Wijkstra, J., Lijmer, J., Balk, F. J., et al (2006) Pharmacological treatment for unipolar psychotic depression: Systematic review and meta-analysis. British Journal of Psychiatry, 188, 410-415.
1.Smith, GC and Pell, JP, Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ, 2003. 327(7429): p. 1459-61.
2.Wijkstra, J, Lijmer, J, Balk, FJ, Geddes, JR, et al., Pharmacological treatment for unipolar psychotic depression: Systematic review and meta-analysis. Br J Psychiatry, 2006. 188: p. 410-415.
3.Treadway, MT, Bossaller, NA, Shelton, RC, and Zald, DH, Effort-based decision-making in major depressive disorder: a translational model of motivational anhedonia. J. Abnorm. Psychol., 2012. 121(3): p. 553-8.
4.Calabrese, JR, Fava, M, Garibaldi, G, Grunze, H, et al., Methodological approaches and magnitude of the clinical unmet need associated with amotivation in mood disorders. J Affect Disord, 2014. 168: p. 439-51.
5.Whitton, E, Treadway, MT, and Pizzagalli, DA, Reward processing dysfunction in major depression, bipolar disorder and schizophrenia. Current opinion in psychiatry, 2015. 28(1): p. 7.
6.Wijkstra, J, Lijmer, J, Burger, H, Cipriani, A, et al., Pharmacological treatment for psychotic depression. Cochrane Database Syst Rev, 2015. 7: p. CD004044.