New review of TCP
I would like to draw everyone’s attention to this significant paper by Sven Ulrich and his co-authors for this most useful and significant paper on TCP .
For this initial rapid response comment I make no apology for citing the abstract of the paper in its entirety
PURPOSE: We conducted a comprehensive meta-analysis of the comparison of tranylcypromine (TCP) and tricyclic antidepressants (TCAs) in the treatment of depression because such work is lacking in medical scientific literature.
METHODS: Literature was searched for studies of TCP controlled by TCAs in multiple databases and in reviews of TCP and monoamine oxidase inhibitors. The natural logarithm of the odds ratio (logOR) and the pooled logOR according to a fixed effect model were calculated for the numbers of responders and nonresponders.
RESULTS: A total of 227 studies of TCP were found including 75 controlled studies of TCP-monotherapy. Twelve of 23 studies of TCP monotherapy and TCAs were excluded for several reasons (duplicates, safety studies, retrospective, cross-over), leaving 11 prospective and parallel controlled studies of TCP monotherapy versus TCAs (6 randomized double-blind). One study was excluded from the meta-analysis because of low quality of study design according to the Food and Drug Administration guidelines of studies of antidepressant drugs and high risk of bias according to the Cochrane’s tool. Two studies with equal efficacy of TCP and TCAs in continuous endpoints did not provide dichotomous response data. A pooled logOR of 0.480 (95% confidence interval, 0.105-0.857, P = 0.01) resulted for the remaining eight studies in the primary meta-analysis, which favors TCP significantly over TCAs (test for heterogeneity: capital HA, Cyrillic = 8.1, df = 7, P > 0.3, not heterogenous; I = 13.6%, heterogeneity not important). The result is robust with respect to inclusion of hypothetical response data of the 2 studies with continuous data only: pooled logOR, 0.350 (95% confidence interval, 0.028-0.672, P = 0.03). Visual inspection of forest plots and subgroup analysis suggest that superiority of TCP over TCAs is determined by 2 studies in psychomotor-retarded (anergic) depression.
CONCLUSIONS: Tranylcypromine and TCAs have an equal antidepressant effect in a mean sample of depressed patients with mixed psychomotor symptoms. Tranylcypromine might be superior to TCAs in depression with predominant psychomotor retardation.
Concerning side-effects, the studies they reviewed indicated:
Significantly lower frequencies occurred in TCP treatment compared with amitriptyline with P < 0.05 or better for tremor, dry mouth as a single reaction, and anticholinergic reactions as a group in one study.25 Significantly higher frequencies resulted for TCP treatment compared with nortriptyline with P < 0.05 or better for dizziness, insomnia, and overexcitement in another study.26 Diastolic (mean values of 77.8 and 88.0 mm Hg, respectively, P < 0.001) and systolic (mean values of 115.6 and 129.3 mm Hg, respectively, P < 0.001) blood pressure…
Tranylcypromine was superior to TCAs in terms of a significantly lower frequency of tremor, constipation, and blurred vision. Tricyclic antidepressants were superior to TCP in terms of a significantly lower frequency of insomnia.
I would also add the comment that the huge advantage of less sexual side-effects does not come out in this analysis for the simple reason that most of the studies making comparisons did not make proper enquiries about sexual side-effects. If you don’t look you won’t see!
Concerning effectiveness in relation to the TCAs
The primary meta-analysis of the comparison of TCP and TCAs as presented in Figure 1 revealed superiority of TCP over TCAs. This is an astonishing result in light of the history of discussion of this topic presented previously.
In my opinion this is only astonishing to people who read (and rely on) papers rather than having actual clinical experience of treating patients. That experience makes it perfectly obvious that TCP is superior to TCAs and other antidepressants.
Concerning efficacy for the ‘anergic’ symptom profile (i.e. more severe ‘biological’ depression)
Superiority of TCP over TCAs in psychomotor-retarded (anergic) depression is in agreement with the pharmacological profile of TCP.
I am pleased, but not surprised, by that conclusion. This is yet further compelling evidence that attaining improvement in these sorts of illnesses requires a drug that significantly elevates dopamine.
I have repeatedly expressed the view that carefully evaluated clinical opinion and experience is superior to many, if not most, drug trials. This review highlights that the superiority of TCP in anergic depression relates to a relatively small number of studies were the total number of patients treated is a fraction of the number of patients I have treated in my career.
One does not need a double-blind trial to recognise that a patient with severe retarded depression has got better, gone home, and gone back to work within a month of starting TCP — despite all the fanfare and pseudoscience, it really is that simple. See the Professor’s story
Almost the only drugs that raise dopamine are MAOIs.
1. Ulrich, S., et al., Efficacy and Adverse Effects of Tranylcypromine and Tricyclic Antidepressants in the Treatment of Depression: A Systematic Review and Comprehensive Meta-analysis. J Clin Psychopharmacol, 2020. 40(1): p. 63-74.
New Review of TCP 2
A once in fifty-year event! A new two-part review (1, 2) of the pharmacology & efficacy of tranylcypromine! ‘Tranylcypromine in mind’.
What is more the full-text is currently freely available here
I cannot describe how pleased I am to see this: it is thorough, authoritative and timely. It adds considerably to my MAOI review (3) which is now a few years old, and my recent editorial (4). It also adds to the ground-swell of information and opinion testifying to the tremendous untapped therapeutic potential of this drug. You might well ask, ‘how can a drug that has been on the market for fifty years possibly have untapped potential’.
The simple answer is, in part: the accidents of history — it reminds me of a story recently, here in Australia, of fossickers going over an old mine site and finding a half-kilo nugget of gold.
I will add a precis of these two TCP papers soon.
Also note a couple of other recent relevant additions to the literature.
Abstracts of recent papers of interest
Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: strategies for the management of treatment-resistant depression (5)
Treatment-resistant depression (TRD) is a major health concern. More than 40% of patients treated for major depressive disorder with an appropriate antidepressant dose for an adequate duration fail to respond. Further, approximately half of adults with major depressive disorder fail to achieve sustained remission despite various medication trials. The utilization of monoamine oxidase inhibitors (MAOIs) for the treatment of depression in clinical practice today is low due to their widely known adverse effects, some of which may be life threatening, and the risk for dietary and drug interactions. For these reasons, MAOIs are not recommended to be prescribed along with other antidepressants or certain prescription or nonprescription drugs. Pharmacologic options are limited for individuals with TRD, however, and there is a paucity of data on the efficacy of MAOIs in combination with other antidepressants for the management of TRD. We performed a search of the PubMed database (inception through January 25, 2015) to identify cases that illustrate the potential utility, as well as risks, of combination treatment with MAOIs and other antidepressants for the management of TRD; 18 articles met the criteria for our search. In addition, we performed a retrospective and my recent editorial (4), case series by reviewing the medical records of 29 adults treated for depression with an MAOI plus another psychotropic agent (an antidepressant or stimulant medication) between 2003 and 2012 at a large Midwestern teaching hospital. We compared the findings of the published experience with our local experience to allow for more informed decisions regarding pharmacotherapy in patients with TRD. We separated the local experience into two groups: 15 cases with the selective MAO type B inhibitor selegiline combined with medications presumed to increase the risk of serotonin syndrome and 14 cases with nonselective MAOIs (phenelzine and tranylcypromine) combined with other contraindicated medications. Although risks of combination treatment certainly exist with selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, or clomipramine, the current literature supports cautious use of combining MAOIs with other antidepressants in patients with TRD who have failed multiple treatment modalities. In addition, the data from the 29 patients receiving combination therapy with an MAOI and another antidepressant or stimulant medication revealed that 21% improved significantly, with no complications. This case series and literature review suggest that when used under close supervision and under the care of an experienced clinician in psychiatry, combination therapy may be a consideration for the management of TRD in patients not responding to monotherapy or other combinations of antidepressants.
Efficacy of Tranylcypromine in Bipolar Depression: A Systematic Review (6)
OBJECTIVE: Currently, there is a paucity of treatment options with limited efficacy for bipolar depression. The monoamine oxidase inhibitor tranylcypromine might be an effective form of treatment. The current systematic review reassesses the efficacy and safety of tranylcypromine in bipolar depression. METHODS: For this systematic review comparing tranylcypromine with placebo or active comparators in bipolar depression, relevant randomized controlled trials were identified from systematic searches of PubMed, EMBASE, and Cochrane library databases. A manual search of the references of the included studies was also performed. RESULTS: Four studies with a total of 145 participants were identified. Response rates were higher in patients treated with tranylcypromine (60.0%-80.7%; overall response rate, 73.7%) compared with placebo, imipramine, and lamotrigine (the latter as add-on to a mood stabilizer) (12.9%-47.6%; overall response rate, 27.5%). The overall switch rate was 6.3% for patients treated with tranylcypromine and 18.4% for patients in the control group. CONCLUSIONS: This systematic review provides evidence for the efficacy and safety of tranylcypromine treatment in bipolar depression. Additional research is required to establish the efficacy of tranylcypromine as add-on to a mood stabilizer.
Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Abeta(1-42)-induced toxicity (7).
Monoamine oxidase (MAO) enzymes play a central role in the pathogenesis of Alzheimer’s disease (AD) and MAO inhibitors (MAOIs) are antidepressant drugs currently studied for their neuroprotective properties in neurodegenerative disorders. In the present work MAOIs such as tranylcypromine [trans-(+)-2-phenylcyclopropanamine, TCP] and its amide derivatives, TCP butyramide (TCP-But) and TCP acetamide (TCP-Ac), were tested for their ability to protect cortical neurons challenged with synthetic amyloid-beta (Abeta)-(1-42) oligomers (100 nM) for 48 h. TCP significantly prevented Abeta-induced neuronal death in a concentration-dependent fashion and was maximally protective only at 10 microM. TCP-But was maximally protective in mixed neuronal cultures at 1 microM, a lower concentration compared to TCP, whereas the new derivative, TCP-Ac, was more efficacious than TCP and TCP-But and significantly protected cortical neurons against Abeta toxicity at nanomolar concentrations (100 nM). Experiments carried out with the Thioflavin-T (Th-T) fluorescence assay for fibril formation showed that TCP and its amide derivatives influenced the early events of the Abeta aggregation process in a concentration-dependent manner. TCP-Ac was more effective than TCP-But and TCP in slowing down the Abeta(1-42) aggregates formation through a lengthening at the lag phase. In our experimental model co-incubation of Abeta(1-42) oligomers with TCP-Ac was able to almost completely prevent Abeta-induced neurodegeneration. These results suggest that inhibition of Abeta oligomer-mediated aggregation significantly contributes to the overall neuroprotective activity of TCP-Ac and also raise the possibility that TCP, and in particular the new compound TCP-Ac, might represent new pharmacological tools to yield neuroprotection in AD.
MAOIs-does the evidence warrant their resurrection? (8)
Objective: The place of monoamine oxidase inhibitors (MAOIs) in psychiatry is reviewed, and the question posed as to whether they are now justifiably disregarded by prescribers. Method: Multiple databases (PubMed, Medline, Embase, Cochrane) were interrogated to provide an overview regarding the use, efficacy and toxicity of MAOIs. Data regarding funded use of these agents in New Zealand were obtained from PHARMAC. Results: Evidence supports the use of MAOIs in major depressive disorder, certain anxiety disorders and, to lesser extent, bipolar depression. Older non-selective agents, such as phenelzine and tranylcypromine, have distinctive efficacy in ‘atypical’ and treatment-resistant depression, but at the cost of serious tolerability problems. Their relegation and perception by clinicians as ‘last resort’ medications – if considered at all – has occurred in the context of various concerns, notably dietary restrictions, potential adverse drug interactions and the usual requirement for divided doses. Conclusions: Sufficient evidence supports consideration of MAOIs in treatment-refractory and atypical depressive disorders, and in social anxiety disorder. Psychiatrists in training need to gain experience in using these agents.
Use of monoamine oxidase inhibitors in chronic neurodegeneration (9)
Introduction: Neurotransmission by biogenic monoamines is important for brain function. Biogenic amine turnover employs the enzymes catechol-O-methyltransferase and monoamine oxidase in neuronal and glial cells. Inhibition of these enzymes elevates biogenic amine levels in the synaptic cleft. Subtype selectivity of inhibition is lost during long-term use of ‘selective’ monoamine oxidase inhibitors. Areas covered: This narrative review discusses use of monoamine oxidase inhibitors in the context with chronic neurodegeneration. Expert opinion: Antidepressant drugs increase synaptic concentrations of biogenic amines. In the aging brain, then one of the two enzymes involved in degrading synaptic amines, catechol-O-methyl transferase, increasingly catalyzes methylation processes. Therefore, metabolism by monoamine oxidase plays an incremental, predominant role in biogenic amine turnover, leading to greater oxidative stress. In patients with chronic neurodegenerative disorders, symptoms, such as depression and apathy, are often treated with drugs that elevate biogenic amine levels. This therapeutic strategy increases biogenic amine turnover, thereby generating neurotoxic aldehydes and enhanced oxidative stress, each of which influence and accelerate the course of neurodegeneration. We propose that antidepressant therapy should be initiated first with monoamine oxidase inhibitors only. If adequate clinical response is not achieved, only then they should be supplemented with a further antidepressant.
1. Ricken, R, Ulrich, S, Schlattmann, P, and Adli, M, Tranylcypromine in mind (Part II): Review of clinical pharmacology and meta-analysis of controlled studies in depression. Eur. Neuropsychopharmacol., 2017.
2. Ulrich, S, Ricken, R, and Adli, M, Tranylcypromine in mind (Part I): Review of pharmacology. Eur. Neuropsychopharmacol., 2017.
3. Gillman, PK, Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors. J Clin Psychopharmacol, 2011. 31(1): p. 66-74.
4. Gillman, PK, “Much ado about nothing”: Monoamine oxidase inhibitors, drug interactions and dietary tyramine. CNS Spectr, 2017: p. http://dx.doi.org/10.1017/S1092852916000651.
5. Thomas, SJ, Shin, M, McInnis, MG, and Bostwick, JR, Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: strategies for the management of treatment-resistant depression. Pharmacotherapy, 2015. 35(4): p. 433-49.
6. Heijnen, WT, De Fruyt, J, Wierdsma, AI, Sienaert, P, et al., Efficacy of Tranylcypromine in Bipolar Depression: A Systematic Review. J Clin Psychopharmacol, 2015. 35(6): p. 700-5.
7. Caraci, F, Pappalardo, G, Basile, L, Giuffrida, A, et al., Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Abeta(1-42)-induced toxicity. Eur J Pharmacol, 2015. 764: p. 256-63.
8. Menkes, D, Bosanac, P, and Castle, D, MAOIs-does the evidence warrant their resurrection? Australasian psychiatry: bulletin of Royal Australian and New Zealand College of Psychiatrists, 2016.
9. Riederer, P and Müller, T, Use of monoamine oxidase inhibitors in chronic neurodegeneration. Expert opinion on drug metabolism & toxicology, 2017. 13(2): p. 233-240.