European Neuropsychopharmacology (2017) 27, 714–731

www.elsevier.com/locate/euroneuro

REVIEW

Tranylcypromine in mind (Part II): Review

of clinical pharmacology and meta-analysis
of controlled studies in depression
Roland Rickena,n, Sven Ulrichb, Peter Schlattmannc, Mazda Adlia

a
Department of Psychiatry and Psychotherapy, Charité, Campus Charité Mitte, Charitéplatz 1,
10117 Berlin, Germany
b
Aristo Pharma GmbH, Wallenroder Str. 8-10, 13435 Berlin, Germany
c
Institute of Medical Statistics, Computer Sciences and Documentation, Jena University Hospital,
Friedrich Schiller University Jena, Bachstraße 18, 07743 Jena, Germany

Received 30 September 2016; received in revised form 13 April 2017; accepted 28 April 2017

KEYWORDS
Tranylcypromine;
Monoamine oxidase
inhibitors;
Monoamine oxidase;
Depression;
Depressive disorder;
Treatment-resistant
Abstract
It has been over 50 years since a review has focused exclusively on the monoamine oxidase
(MAO) inhibitor tranylcypromine (TCP). A new review has therefore been conducted for TCP in
two parts which are written to be read preferably in close conjunction: part I – pharmacody-
namics, pharmacokinetics, drug interactions, toxicology; and part II – clinical studies with
meta-analysis of controlled studies in depression, practice of TCP treatment, place in therapy.
The irreversible and nonselective MAO-A/B inhibitor TCP has been confirmed as an efficacious
and safe antidepressant drug. For the first time, a meta-analysis of controlled clinical trials in
depression demonstrated that TCP is superior to placebo (pooled logOR = 0.509, 95%CI = 0.026
to 0.993, 4 studies) and equal to other antidepressants (pooled logOR = 0.208, 95%CI = 0.128
to 0.544, 10 studies). In treatment resistant depression (TRD) after tricyclic antidepressants
(TCAs) and selective serotonin reuptake inhibitors (SSRIs), TCP was superior to placebo
(logOR = 2.826, 95%CI = 1.494 to 4.158, one study) and non-established antidepressants
(pooled logOR = 1.976, 95%CI = 0.907 to 3.045, 4 studies), and was equal to other MAO
inhibitors and an antidepressant combination (pooled logOR = 0.366, 95%CI = 0.869 to
0.137, 4 studies). Controlled studies revealed that TCP might provide a special advantage in the
treatment of atypical depression, which was supported by a recent PET study of MAO-A activity
in brain. However, TCP treatment remains beset with the need for a mandatory tyramine-
restricted diet and is therefore limited to use as a third-line antidepressant according to recent
treatment algorithms and guidelines for depression treatment. On the other hand, the effort
needed to maintain a tyramine-restricted diet may have been overestimated in the perception

n
Corresponding author.
E-mail address: roland.ricken@charite.de (R. Ricken).

http://dx.doi.org/10.1016/j.euroneuro.2017.04.003
0924-977X/& 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Depression in the perspective of a MAO inhibitor 715

of both doctors and patients, which may have led to relative underuse of TCP. Interaction with
serotonergic drugs bears the risk of severe serotonin toxicity (SST) and combination with
indirect sympathomimetic drugs may result in hypertensive crisis which both adds to the risks of
TCP. At the same time, TCP has low to no risks of central anticholinergic, sedative, cardiac
conduction, body weight, hemostatic effects, or pharmacokinetic drug interactions. Neuropro-
tection by MAO inhibitors due to reduced oxidative stress is becoming increasingly studied.
Taken together, TCP is being increasingly recognized as an important option in systematic
treatment approaches for patients suffering from severe courses of depression, such as TRD and
atypical depression, by offering a MAO-related pathophysiological rationale.
& 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction
A general introduction to this review part II on tranylcypro-
mine (TCP) has already been given in part I (pharmacology)
of the joined reviews. Consecutively, the main data of the
clinical pharmacology of TCP are presented here which
includes, for the first time, a meta-analysis of controlled
studies in depression. A discussion of the clinical practice of
TCP treatment is added referring to special requirements of
this irreversible monoamine oxidase (MAO)-A/B inhibitor.
This is completed by an overview of the state of the art
discussion in medical literature concerning the benefit-risk
ratio and place in therapy of TCP.
2. Experimental procedures
The experimental procedures of the review have already been
presented in part I.
For the meta-analysis, controlled studies of TCP monotherapy in
depression have been identified from tabular compilations in two
comprehensive reviews covering the periods before 1965 (Atkinson and
Ditman, 1965) and before 1993 (Thase et al., 1995). Considering these
studies in the previous reviews was regarded as a sufficient quality
standard; however, no violations in minimal quality requirements for
the target of this meta-analysis were detected in our own evaluation
(prospective parallel or cross-over, open, single-blind or double-blind
study, placebo or active drug comparator, only depressive patients,
acute treatment, no antidepressant comedication, sufficient descrip-
tion, and minimum of 10 patients). Studies after 1993 were searched
in MedLine using the search terms tranylcypromine and depression.
Data of published study reports have been extracted and documented
by one author (SU) and the file has been confirmed by another author
(RR). Six studies were found that compared TCP with placebo
(Bartholomew, 1962; Glick, 1964; Gottfries, 1963; Khanna et al.,
1963; Himmelhoch et al., 1982; White et al., 1984) and 19 studies with
active comparator: the TCAs imipramine (Freyhan, 1960; Himmelhoch
et al., 1991; Spear et al., 1964; Thase et al., 1992a), amitriptyline
(O'Brien et al., 1993; Razani et al., 1983; White et al., 1980a),
imipramine and amitriptyline (Richmond and Roberts, 1964), and
nortriptyline (White et al., 1984), the MAO inhibitors phenelzine
(Birkenhäger et al., 2004; Glick, 1964), brofaromine (Nolen et al.,
1993; Volz et al., 1994a, 1994b), and moclobemide (Heinze et al.,
1993), the serotonin precursor L-5-hydroxytryptophan (Nolen et al.,
1985), the dopamine and norepinephrine reuptake inhibitor nomifen-
sine (Nolen et al., 1988), the combination of venlafaxine and
mirtazapine (McGrath et al., 2006), and lamotrigine (Nolen et al.,
2007). Eight studies were conducted between 1960 and 1964 (early
studies). The remaining 17 studies all were conducted between 1980
and 2007 (late studies). Of the 25 studies, 17 were double-blind
randomized trials, 5 early studies (62.5% of early studies) and 12 late
studies (70.6% of late studies). One study was single-blind, 5 studies
were open label, and 22 were randomized. Modern criteria of
psychiatric diagnosis, such as Diagnostic and Statistical Manual of
Mental Disorders (DSM III or IV) were used in the studies after 1980.
Only 4 studies did not use a structured and validated rating scale, such
as the Hamilton Depression Scale (HAMD). As these were early studies,
this marks the only important difference between early and late
studies. It is therefore concluded that the quality of studies was high
for the 1536 patients included, with 664 patients receiving TCP
(Tables 1, 2).
The effect size of studies was calculated as the log odds ratio
(logOR) of the number of treatment responders and nonresponders in
TCP and control group, which were categorized according to 50%
HAMD improvement as a cut-off point in the majority of studies or
according to a predefined level of Clinical Global Impression (CGI)
improvement or similar in the remaining studies. A standard continuity
correction of 0.5 was applied to one study that included nil cells. All
patients randomized or later defined as drop-outs were included in the
analysis (intention-to-treat sample; ITT). Drop-outs were set as
nonresponders for studies lacking these detailed data. In three studies
without ITT data, transformation of completer's data to ITT data
according to the mean ratio of completer's and ITT data of the other
studies was needed. The summary effect size was calculated as the
pooled logOR according to a fixed effect model in a Microsoft Excel
spreadsheet (D'Agostino and Weintraub, 1995; Neyeloff et al., 2012).
In the case of heterogeneity of studies, explorative sensitivity
analyses were conducted with respect to subgroups of studies using
treatment resistant depression (TRD) versus non-TRD in a first
approach and pharmacological group of comparator drug as a
second approach for group parameters to obtain homogeneous data
sets. This resulted in four pooled odds ratios according to homo-
geneous data sets for TCP versus placebo in non-TRD, TCP versus
comparator antidepressant in non-TRD, and two times for TCP
versus comparator antidepressant in TRD according to two different
drug groups.
3. Clinical studies and therapeutic experience
with tranylcypromine
3.1. Meta-analysis of prospective controlled
studies in depression
Meta-analyses of TCP in depression including formal statis-
tical calculations of overall effect size (e.g., with pooled
odds ratios), are currently lacking in the literature. There-
fore, we conducted a meta-analysis to compare TCP with
other antidepressants and placebo. Experimental
716 R. Ricken et al.

Table 1 Compilation of patient data in controlled studies of the meta-analysis of tranylcypromine (TCP) in depression.

Study Depression subtypes Agea (years) Sex Hospitalization

Freyhan, 1960 n.d. 57 m/f in

Bartholomew, 1962 Reactive, endogenous, involutional 25–67 m/f out
Gottfries, 1963 Endogenous, neurotic, other n.d. n.d. in
Khanna et al., 1963 n.d. 24–47 f in
Spear et al., 1964 Endogenous, atypical 44.5 m/f in/out
Richmond and Roberts, 1964 Endogenous, atypical n.d. n.d. out
Glick, 1964 Involutional, reactive, neurotic 48.5 m/f out
White et al., 1980a MD, minor depression, several subtypes 33 (19–61) m/f in
Himmelhoch et al., 1982 Anergic, 29 bipolar, RVS, TRD to TCA 37.4711.6 m/f out
Razani et al., 1983 MD, 22 of 60 endogenous 41712.8 m/f in/out
White et al., 1984 Nonendogenous (80%), endogenous (20%) 37 (18-60) m/f out
Nolen et al., 1985 MD, TRD to SSRI/TCA 20-65 m/f n.d.
Nolen et al., 1988 MD, TRD to SSRI/TCA 20-65 m/f n.d.
Himmelhoch et al., 1991 Anergic BD, RVS 40.2711.6 m/f out
Thase et al., 1992a Anergic BD, RVS, TRD to Imi 37.7712.7 m/f out
Heinze et al., 1993 ICD-9 Depression, endogenous unipolar 47.2712.3 m/f in/out
Nolen et al., 1993 MD, TRD to TCA 48.8710.7 m/f in
O’Brien et al., 1993 MD 18–65 m/f in
Volz et al., 1994a MD, TRD to TCA/SSRI 42.4 (18–67) m/f in
Volz et al., 1994b Nonendogenous 18-65 m/f in
Birkenhäger et al., 2004 MD, TRD to TCA/SSRI 18-65 m/f in
McGrath et al., 2006 TRD to SSRI/SSNRI/TCA/augmentation 46.0711.1 m/f out
Nolen et al., 2007 TRD to SSRI/SSNRI/TCA/Bupropion, BD 46.2712.9 m/f n.d.

MD major depression, TRD treatment resistant depression, BD bipolar depression, RVS reversed neurovegetative symptoms, m male,
f female, in inpatients, out outpatients, n.d. not defined.
a
Mean, range, mean (range) or mean 7 standard deviation.

procedures are described in paragraph 2. The results of
individual studies are summarized in Table 3.
3.1.1. Comparison with placebo in depression
Accordingly, the comparison with placebo in 5 studies
(no data available in one other study) revealed a pooled
logOR = 0.779 with 95% confidence interval (CI) = 0.324 to
1.233 not crossing zero. However, the set of data was
inhomogeneous with Χ2 = 10.9, df = 4, and p o 0.05
because of one outlier placebo controlled study in TRD
showing a very high effect size of logOR = 2.826 and 95%
CI = 1.494 to 4.158 (Himmelhoch et al., 1982). Excluding this
study, however, still provided a pooled logOR = 0.509 with
95%CI = 0.026 to 0.993 not crossing zero and formal con-
firmation of homogeneity (Χ2 = 0.64, df = 3, p 4 0.05). This
is at the upper end of the effect size of antidepressants
compared to placebo of 0.39 (95%CI 0.24 to 0.54) (Bauer
et al., 2013). The one study without available data for the
meta-analysis also estimated TCP being more efficacious than
placebo (Khanna et al., 1963). TCP is therefore superior to
placebo in the treatment of depression at a p = 0.05
significance level (Figure 1).
3.1.2. Comparison with antidepressants in depression
other than treatment resistant depression (TRD).
The comparison with antidepressant drugs in 18 studies (no data
available in one other study) resulted in a pooled logOR = 0.156
with 95%CI = -0.114 to 0.426 crossing zero and formal
inhomogeneity of the data set (Χ2 = 29.72, df = 17,
po0.05). Excluding eight of these studies which were done in
TRD, the picture remained similar, however, whereby formal
homogeneity was confirmed (pooled logOR = 0.208 with 95%
CI = -0.128 to 0.544; homogeneity: Χ2 = 10.31, df = 9,
p40.05). The one study without available data for the meta-
analysis also estimated TCP being as efficacious as imipramine
(Spear et al., 1964). Therefore, we conclude, based on the
comparator drugs investigated in this sample, that TCP is as
efficacious as TCAs and other MAO inhibitors in non-TRD
(Figure 2).
3.1.3. Comparison with antidepressants in treatment
resistant depression (TRD)
The comparator drugs were more variable in studies of TRD.
A plausible subgrouping was therefore conducted according
to the therapeutic status as established or non-established
antidepressant (or antidepressant combination, or sequence
of antidepressants). Nevertheless, this remains a rather
artificial and subjective approach. Thus, an antidepressant
drug combination (McGrath et al., 2006) and MAO inhibitors
(Birkenhäger et al., 2004; Nolen et al., 1993; Volz et al.,
1994a) (active comparator in TRD: group 1) as well as L-5-
hydroxytryptophan (Nolen et al., 1985), nomifensine (Nolen
et al., 1988), lamotrigine (Nolen et al., 2007), and a small
study of a TCA after non-response to TCP in cross-over design
(Thase et al., 1992a) (active comparator in TRD: group 2)
formed the two subgroups. Formal inhomogeneity resulted in
a combined analysis, and homogeneous data sets resulted in
 Depression in the perspective of a MAO inhibitor
Table 2 Compilation of methods used in controlled studies of the meta-analysis of tranylcypromine (TCP) in depression.

Study Double- Randomized Number of Control TCP dosea (mg/ Duration Comedication Validated Depres- Drop-outs (%)
blind patients day) (weeks) sion Scale

TCP Control TCP Control

Freyhan, 1960 No No 14 108 Imi 30–150 5–193 No No n.d. n.d.

Bartholomew, 1962 Yes Yes 51 51 Placebo 30–60 6 Sedatives No 17.6 17.6
Gottfries, 1963 Yes No 25 25 Placebo 15–30 2–6 Sedatives No n.d n.d.
Khanna et al., 1963 Yes Yes 15 15 Placebo 30 2 No Yes 0.0 6.7
Spear et al., 1964 Yes Yes 37 41 Imi 30 3 Sedatives No 8.1 12.2
Richmond and Nob Yes 20 40 Imi, Ami 40 3 Barbiturates Yes n.d. n.d.
Roberts, 1964
Glick, 1964 Yes Yes 9 13 Placebo 37 4 Sedatives Yes 55.6 53.8
13 Phe 53.8
White et al., 1980a No Yes 11 9 Ami 30 4 n.d. Yes 9.1 11.1
Himmelhoch et al., Yes Yes 28 31 Placebo 40 6 Flurazepam Yes 21.4 45.2
1982
Razani et al., 1983 Yes Yes 21 30 Ami 40 4 n.d. Yes 19.0 30.0
White et al., 1984 Yes Yes 63 59 Placebo 44.4 (30–60) 4 Sedatives, analgesics, Yes 41.3 23.7
61 Nor antihistamines 34.4
Nolen et al., 1985 No Yes 26 17 5HTP 82 (60–100) 4 Lorazepam Yes 0.0 5.9
Nolen et al., 1988 Yes n.d. 19 15 Nom 78 (40–100) 4 Lorazepam Yes 10.5 6.7
Himmelhoch et al., Yes Yes 28 28 Imi 36.8711.9 6 n.d. Yes 7.1 25.0
1991
Thase et al., 1992a Yes Yes 12 4 Imi (after 39.2 (20–60) 6 n.d. Yes 0.0 50.0
TCP)
Heinze et al., 1993 Yes Yes 79 81 Moc 24.375.9 44 Sedatives Yes 15.2 4.9
Nolen et al., 1993 Yes Yes 17 22 Bro 81.2725.9 4 Lorazepam Yes 11.8 0.0
O'Brien et al., 1993 Yes Yes 26 28 Ami 22.477.8 6 Benzodiazepines Yes 19.2 25.0
Volz et al., 1994a Yes Yes 47 46 Bro 20–30 6 Sedatives Yes 8.5 8.7
Volz et al., 1994b Yes Yes 11 35 Bro 20 4 Sedatives Yes 18.2 8.6
Birkenhäger et al., Yes Yes 39 38 Phe 60.6 (30–100) 5 Lorazepam Yes 7.7 18.4
2004
McGrath et al., 2006 No Yes 58 51 Ven + Mir 36.9 12 n.d. Yes 41.4 21.6
Nolen et al., 2007 No Yes 8 11 Lam 20–100 10 Li, VPA, CBZ Yes 25.0 54.5

Abbreviations of drugs as in figures, n.d. not defined.

a
mean, range, mean (range) or mean 7 standard deviation.
b
single blind.

717
718 R. Ricken et al.

Table 3 Results of controlled studies of tranylcypromine (TCP) in depression.

Study Control TCP Control logOR LL(logOR) UL(logOR)

R (ITT) NR (ITT) R (ITT) NR (ITT)

Freyhan, 1960 Imi 6 8 60 48 0.52 1.64 0.61

Bartholomew, 1962 Placebo 28 23 20 31 0.63 0.15 1.42
Gottfries, 1963 Placebo 10 15 7 18 0.54 0.65 1.72
Khanna et al., 1963 Placebo n.d. No calculation possible.
Spear et al., 1964 Imi n.d. No calculation possible.
Richmond and Roberts, 1964 Imi, Ami 8 12 9 31 0.83 0.33 1.99
Glick, 1964 Placebo 2 7 1 12 1.23 1.34 3.81
Phe 3 10 0.05 2.08 1.98
White et al., 1980a Ami 8 3 7 2 0.27 2.33 1.78
Himmelhoch et al., 1982 Placebo 20 8 4 27 2.83 1.49 4.16
Razani et al., 1983 Ami 13 8 16 14 0.35 0.78 1.49
White et al., 1984 Placebo 25 38 19 40 0.32 0.42 1.07
Nor 25 36 0.05 0.77 0.66
Nolen et al., 1985 5HTP 15 11 0 17 3.85 0.94 6.77
Nolen et al., 1988 Nom 10 9 2 13 1.98 0.24 3.72
Himmelhoch et al., 1991 Imi 21 7 10 18 1.69 0.53 2.84
Thase et al., 1992a Imi (after TCP) 9 3 1 3 2.20 0.42 4.81
Heinze et al., 1993 Moc 59 20 60 21 0.03 0.68 0.74
Nolen et al., 1993 Bro 5 12 10 12 0.69 2.03 0.65
O'Brien et al., 1993 Ami 15 11 14 14 0.31 0.76 1.38
Volz et al., 1994a Bro 34 13 34 12 0.08 1.00 0.84
Volz et al., 1994b Bro 6 5 20 15 0.10 1.47 1.26
Birkenhäger et al., 2004 Phe 17 22 18 20 0.15 1.05 0.75
McGrath et al., 2006 Ven + Mir 7 51 12 39 0.81 1.83 0.21
Nolen et al., 2007 Lam 5 3 4 7 1.07 0.82 2.96

R number of responders, NR number of nonresponders, ITT intention to treat, LL(logOR), UL(logOR) lower and upper limit (95%CI) of
log odds ratio, abbreviations of drugs as in figures, n.d. not defined.

separate meta-analyses of the two drug groups. TCP was

Figure 1 Effect sizes and summary effect sizes calculated as
log odds ratios and pooled log odds ratios as well as their 95%
confidence intervals for clinical studies of tranylcypromine
and placebo in depression (*non-homogenous, study (5) in
treatment resistant depression, the numbers above confi-
dence intervals indicate the numbers of responders and
non-responders after tranylcypromine (first pair) and placebo
(second pair)).
equal to comparators in the meta-analysis with MAO inhibi-
tors and drug combination (group 1: pooled logOR = -0.366
with 95%CI = -0.869 to 0.137; homogeneity: Χ2 = 1.54,
df = 3, p 4 0.05), and it was clearly superior to the non-
or less established antidepressants, including TCA after TCP
(group 2: pooled logOR = 1.976 with 95%CI = 0.907 to 3.045;
homogeneity: Χ2 = 2.51, df = 3, p 4 0.05) (Figure 3).
A comparison of these results with a meta-analysis pub-
lished in 1995, which included studies conducted until 1992, is
difficult because the database had 10 fewer studies and
subgrouping of studies according to in- and outpatients only.
TCP response was higher than placebo and active comparators
in all tests; however, there was no confirmation of statistical
significance (Thase et al., 1995). As a general conclusion of
the present meta-analysis with calculation of pooled odds
ratios, TCP exhibited clear antidepressant activity in the
clinical assessment, which was superior to placebo and similar
to the active comparator. Unfortunately, no controlled studies
have been conducted to compare TCP with antidepressants
introduced after 1985, such as SSRIs, SSNRIs, mirtazapine,
trazodone, bupropion, or agomelatine.
Depression in the perspective of a MAO inhibitor
Figure 2 Effect sizes and summary effect size calculated as
log odds ratios and pooled log odds ratio as well as their 95%
confidence intervals for clinical studies of tranylcypromine and
antidepressant comparator drugs in depression (Imi = imipra-
mine, Ami = amitriptyline, Phe = phenelzine, Nor = nortripty-
line, Moc = moclobemide, Bro = brofaromine; the numbers
above confidence intervals indicate the numbers of responders
and nonresponders after tranylcypromine (first pair) and com-
parator antidepressant drug (second pair)).
3.2. Non-interventional clinical studies to
compare the efficacy of tranylcypromine with SSRIs
and moclobemide in depression
In a practice-based observational study conducted in
Canada, 213 DSM-III depressed outpatients were investi-
gated in 2677 visits by means of the Montgomery-Asberg
Depression Rating Scale (MADRS) and survival statistics over
two years. Time to MADRS below a cut-off of 18 was
significantly lower for treatment with MAO inhibitors (61%
TCP) or TCAs compared to SSRIs and a heterogeneous group
of “atypical” antidepressants (71% bupropion), and the
overall time spent below the cut-off was longer for MAO
inhibitors and TCAs (Mittmann et al., 1999). An Australian
study over 12 months in DSM-IV depressive patients of the
more severe and treatment resistant type also compared
irreversible MAO inhibitors (n = 18 treatments), TCAs
(n = 67), SSRIs (n = 71), and moclobemide (n = 22). Irre-
versible MAO inhibitors among drug groups received the
highest rating as a helpful intervention (56%), had the
highest ratio of full remission among the ratings as helpful
intervention (53%), and received the lowest ratings that
spontaneous remission may have been added (17%) or
concomitant treatment was more likely to be responsible
(11%) to the treatment effect. For example, the corre-
sponding ratios were 48%, 29%, 56%, and 23% for SSRIs. The
data were evaluated by the authors as suggestive of an
advantage in efficacy for irreversible MAO inhibitors and
TCAs over SSRIs and moclobemide (Parker et al., 2001). A
retrospective analysis of the data from a trial in bipolar
depression revealed a recovery rate of 53% for 30 patients
on TCP, but only 27% for 22 patients on paroxetine, with a
significant difference in the survival statistics (p = 0.029)
(Mallinger et al., 2009). Switch studies of TCP to moclobe-
mide, which seemed to be a reasonable approach after the
development of the reversible MAO inhibitor, resulted in a
disappointing outcome in two studies. For example, in 30
stable patients receiving 10–20 mg/day TCP, 28 suffered
719
Figure 3 Effect sizes and summary effect sizes calculated as
log odds ratios and pooled log odds ratios as well as their 95%
confidence intervals for clinical studies of tranylcypromine and
antidepressant comparator drugs (group 1: MAO inhibitors and
antidepressant combination, group 2: not established antide-
pressants and imipramine after TCP) in treatment resistant
depression (Bro = brofaromine, Phe = phenelzine, Ven = ven-
lafaxine, Mir = mirtazapine, 5HTP = 5-hydroxytryptophan,
Nom = nomifensine, Imi = imipramine, Lam = lamotrigine;
the numbers above confidence intervals indicate the numbers
of responders and nonresponders after tranylcypromine (first
pair) and comparator antidepressant drug (second pair)).
from a relapse after the switch to 450–600 mg/day moclo-
bemide (Gosciniak, 1997; Vink et al., 1994). Our literature
search in MedLine using the search term tranylcypromine
revealed no other studies comparing TCP with SSRIs or other
antidepressants typically used in most patients today.
3.3. Tranylcypromine in subtypes of depression
A good chance for a differential treatment of depression is
theoretically expected for TCP because it displays a special
mechanism of action and is at the extreme for psychomotor
activating and non-sedating properties of antidepressants.
Recent studies of MAO in the pathophysiology of depression
as presented in paragraph 3.1 of review part I support this
rationale. However, the intersection of diagnostic criteria,
changes in terminology, a limited number of studies, and
variability in study design complicated the definition of
subtypes of depression, which may be preferentially treated
by TCP.
3.3.1. Atypical depression
Atypical depression in terms of reversed neurovegetative
symptoms (anergia, motor retardation, hyperphagia, and
hypersomnia), mood reactivity, and interpersonal rejection
sensitivity, which was previously considered as reactive or
non-endogenous depression (including diagnostic differ-
ences), was even linked to a good MAO inhibitor response
in the definitions by some authors (Pae et al., 2009; Parker
et al., 2002). A recent study thus confirmed increased MAO-
A activity for this subtype of depressive disorders
(Chiuccariello et al., 2014). Increased platelet MAO-B
activity has already been reported in previous studies
(White et al., 1980b) and differentiation of atypical depres-
sion as a genetically-specific subtype related to MAO
720
inhibitor response has been previously hypothesized by
family correlations (Pare and Mack, 1971). Three controlled
studies have been conducted by one group of researchers
for TCP exclusively in patients meeting the above criteria of
atypical depression. The comparison of TCP (n = 28) with
placebo (n = 31) resulted in 71.4% versus 12.9% responders,
respectively (p o 0.001) (Himmelhoch et al., 1982), and a
comparison of TCP (n = 28) with imipramine (n = 28)
resulted in 75.0% versus 35.7% responders, respectively
(p o 0.01; logOR = 1.69 with 95%CI = 0.53 to 2.84)
(Himmelhoch et al., 1991). A small study of 12 patients
with TCP and 4 patients with imipramine revealed 75%
versus 25% responders, respectively (p = 0.07) (Thase
et al., 1992a). One limitation of these studies is the
inclusion of only bipolar, atypical depression in two studies
and the lack of confirmation by other research groups. In a
non-controlled study of 40 patients, TCP in doses of 20–
60 mg/day resulted in a superior rate of responders of a
subgroup with intersection of atypical and anergic charac-
teristics (n = 27) compared to a subgroup with typical
characteristics (n = 13; rate of responders 67% and 31%,
respectively; p o 0.05) (Thase et al., 1992b). The previous
review of TCP, which was limited to data from 1965,
concluded that TCP may be useful in reactive and psycho-
neurotic depression, which are diagnostic entities similar to
the recent definition of atypical depression (Atkinson and
Ditman, 1965). Double blind, randomized, and controlled
trials have been conducted exclusively in patients with
atypical depression for other MAO inhibitors and confirmed
superior efficacy (e.g., phenelzine) (Krishnan, 2007;
McGrath et al., 1987). Taken together, these clinical,
pathophysiological, and therapeutic data indicate a possible
special quality of TCP in atypical depression.
3.3.2. Bipolar depression
Bipolar depression, as defined primarily by its time course
with periods of mania or mixed episodes, may consist of
anergic and atypical characteristics in a predominant por-
tion of patients (Akiskal and Benazzi, 2005; APA, 2010;
Grunze et al., 2010; Mitchell et al., 2008). Some studies of
TCP were even conducted in patients meeting both the
bipolar and atypical characteristics and are therefore
included already in the previous paragraph (Himmelhoch
et al., 1991; Thase et al., 1992a). An additional study
enrolled bipolar patients but without concomitant atypical
depression (Nolen et al., 2007). Half of the patients in the
placebo controlled study of 59 patients already discussed
above for atypical depression suffered from bipolar depres-
sion with very good treatment effect of TCP [logOR = 2.83
with 95%CI = 1.49 to 4.16, TCP to placebo response-rate
ratio (RR) = 5.5 with 95%CI = 2.1 to 14.2] (Himmelhoch
et al., 1982). Although this single study should not be
overestimated, a recent systematic review of these 4 studies
confirmed good efficacy and safety of TCP in bipolar
depression (Heijnen et al., 2015). A recent meta-analysis
of placebo controlled studies in bipolar depression of all
antidepressants calculated a mean antidepressant to pla-
cebo RR = 1.43 with 95%CI = 1.11 to 1.84, which included a
phenelzine study with phenelzine to placebo RR = 2.29 with
95% CI = 0.97 to 5.4 (Vazquez et al., 2013). A retrospective
analysis of a large study of patients with bipolar disorder
R. Ricken et al.
and bipolar depression was mentioned in paragraph 3.2 and
found superior efficacy of TCP compared to paroxetine
(Mallinger et al., 2009). Current evidence suggests that
TCP and other MAO inhibitors may only have a low risk of
inducing switch into mania (Heijnen et al., 2015; Truman
et al., 2007; Vazquez et al., 2013).
3.3.3. Treatment-resistant depression
Therapeutic experience and non-controlled open studies
suggest a therapeutic benefit from TCP in patients resis-
tant to adequate TCA treatment (Adli et al., 2002; Thase
et al., 1992b). A recent study found 25% remission in 28
patients receiving 56 7 12 mg/day TCP for 8.9 7 2.6
weeks (mean 7 standard deviation) after a mean number
of 7 treatments with SSRIs, SSNRIs, bupropion, TCAs, and
others (Stewart et al., 2014). A retrospective chart review
of 32 university psychiatric clinic patients receiving an
intensive TCP treatment [i.e., mean dose of 51.9 mg/day
(20 to 100 mg/day), multiple comedications if needed,
and a mean duration of treatment of 6.5 weeks (1 to 29
weeks)] reported 59.4% of patients in remission and 81%
responders (Adli et al., 2008). The meta-analysis of
controlled studies presented in paragraph 3.1 and
Figures 1 and 3 clearly confirmed the efficacy of TCP in
TRD after failure on TCAs and SSRIs. The STAR*D-study
with a responder ratio of only 12.1% (McGrath et al., 2006)
takes an outlier position among other TCP-studies in TRD
(mean responder ratio 58.1% (29.4–75.0)) (Birkenhäger
et al., 2004; Himmelhoch et al., 1982; Nolen et al.,
1985, 1988, 1993, 2007; Thase et al., 1992a; Volz et al.
1994a). This may be explained by a nocebo effect for TCP
in the STAR*D-study because it was stated explicitly that
doctors and patients were uncomfortable with the MAO
inhibitor in this open-label study. And the mean TCP dose
in the STAR*D-study with 36.9 mg/day was the second
lowest among TCP-studies in TRD. However, no antide-
pressant switch study has been conducted with a control
of TCP by continuing the previous antidepressant. Since
the introduction of the SSRIs in the 1980s, TCP has been
mainly used in TRD because of the mandatory tyramine-
reduced diet and risk of hypertensive crisis, which limits
TCP to a third line treatment. Some authors consider TCP
as a first choice in stage-3 TRD according to the Thase and
Rush classification (Birkenhäger et al., 2004). A recent
review questioned the practice of using MAO inhibitors
after multiple failed trials only, by stating “The use of
MAOI agents should not be a treatment of last resort after
10–12 failed antidepressant trials … “ (Schwartz, 2013).
3.3.4. Depression with special psychopathologic
characteristics
Several case series on the successful treatment of special
subtypes of depression with TCP have been published such
as winter depression (Dilsaver, 1990), delusional depression
(Lieb and Collins, 1978), recurrent brief depression (Joffe,
1996), and melancholic depression (McGrath et al., 1984).
An inspection of these reports revealed, however, that many
patients simultaneously shared diagnostic criteria of atypi-
cal and bipolar depression as well as TRD. Thus, this may
have been more relevant for the success of TCP.
Depression in the perspective of a MAO inhibitor
3.4. Tranylcypromine adjuvant to antipsychotic
drugs in negative syndrome of schizophrenia
The use of TCP as a “psychic energizer” and an adjuvant to
antipsychotic drugs, mainly trifluoperazine, has been
reported in so-called defect schizophrenia as early as 1960
(Kruse, 1960; Singh and Free, 1960). A pharmacoepidemio-
logic study in two German university clinics revealed in 1994
that 8% of TCP patients were suffering from schizophrenia
(Schmidt et al., 1994). This approach has been supported on
a clinical and theoretical basis by the observation that
atypical depression shares some characteristics with schizo-
phrenia with negative symptoms (Parker et al., 2002) and by
the hypothesis of dopaminergic and norepinephrinergic
hypofrontality (Da Silva et al., 2008). TCP is expected to
improve negative schizophrenia by increasing prefrontal
cortex dopamine and norepinephrine neurotransmission. A
controlled study published in 1987 included 30 chronic
schizophrenic outpatients with predominant emotional
withdrawal, motor retardation, and blunted affect and only
minimal positive symptoms. Patients were treated with
300 mg/day chlorpromazine, whereas half each received
adjuvant 20 mg/day TCP or placebo over 4 months.
Improvement was observed in 11 patients on TCP (73%)
and no patients on placebo. After switching the placebo
group to TCP for an additional 4 months, 13 patients (87%)
showed improvement. Taking into account 10 previous
studies, including 6 controlled (Buffaloe and Sandifer,
1961; Hedberg et al., 1971; Hordern et al., 1962; Mena
et al., 1964; Schiele et al., 1963; Vogt, 1961) and 4 open
(Barsa and Saunders, 1962; Bucci, 1969; Kruse, 1960; Singh
and Free, 1960) studies, the authors concluded that label-
ling TCP only as an antidepressant is misleading (Bucci,
1987). A recent non-interventional surveillance study of 53
patients investigated this approach for adjuvant TCP with
second generation antipsychotic drugs. Improved impulse in
20 patients was found as a minor benefit of adjuvant TCP
after ineffective trials with adjuvant SSRIs. The optimum
treatment was defined for negative schizophrenic patients
with no or minimal positive symptoms, TCP dose no more
than 40 mg/day, antipsychotics at medium dose, no benzo-
diazepines, and a minimum duration of treatment of 2 to
3 months. The risk of exacerbation of positive symptoms
was found to be very low and patients were considered to
be compliant with the tyramine-restricted diet (Roesch-Ely
et al., 2011). Nevertheless, controlled trials are needed for
a better definition of the benefit-risk ratio of TCP in
negative schizophrenia.
3.5. Tranylcypromine in other psychiatric
disorders
Parameters associated with increased MAO-A activity (e.g.,
increased MAO-A gene promoter alleles) have also been
found in panic disorder and other neuropsychiatric disorders
(Deckert et al., 1999; Naoi et al., 2016). Therefore, if
pharmacotherapy is instituted, some published cases and
cases series suggest good experience with TCP as an
alternative in selected patients of obsessive-compulsive
721
disorder (Erfurth and Schmauss, 1993; Jenike, 1981), anxi-
ety with agoraphobia and panic disorder (Boerner and
Luehring, 2010; Ries and Wittkowsky, 1986; Tyrer and
Shawcross, 1988), social phobia (Versiani et al., 1988),
borderline personality disorder (Cowdry and Gardner,
1988), and narcolepsy (Clemons et al., 2004; Gernaat
et al., 1995). No controlled studies have been conducted,
with the exception of one study in social anxiety disorder,
which resulted in 70% of patients receiving 30 mg/day or
60 mg/day TCP over 12 weeks being free of panic attacks
(Nardi et al., 2010). Better data in terms of controlled trials
are available for phenelzine (Blanco et al., 2013) and TCP in
addition to phenelzine is therefore included in national and
international treatment guidelines of anxiety disorders
(Bandelow et al., 2008). TCP is used for these conditions
as a reserve treatment only by experienced psychiatrists,
however, also known “in these cases as very useful”. It is
suggested that the therapeutic effect is derived not only
from MAO inhibition with subsequent enhanced serotonergic
and norepinephrinergic tone in the CNS, but also from
additional mechanisms such as norepinephrine reuptake
inhibition. Whether comorbid depression may be a predictor
of good or poor response has not been clarified.
3.6. Tranylcypromine in neurology
Neuroprotection by MAO inhibitors is a growing area in
neuropharmacology research because reduced metabolic
burden by neurotransmitter metabolites and reactive oxygen
species is inherent to inhibition of amine metabolism (Baker
et al., 2007). In addition, TCP, similar to other MAO-A/B and
MAO-B inhibitors, was shown to protect against 1-methyl-4-
phenyl-1,2,5,6-tetrahydropyridine (MPTP)-induced dopami-
nergic neurotoxicity (Heikkila et al., 1984) and is known to
increase dopamine levels. TCP was therefore expected to be
effective in studies of Parkinson's disease. One study found
that 30 mg/day TCP used instead of the selective MAO-B
inhibitor selegiline slightly improved early signs and symp-
toms in 37 patients with Parkinson's disease who did not
require levodopa treatment, and only minimal progression
was observed over 33 months. In addition, an indirect
comparison with historic data in similar patients for selegiline
or tocopherol (vitamin E) treatment found a higher number
of patients requiring levodopa with selegiline. Comorbid
depression could be treated successfully with TCP (Fahn
and Chouinard, 1998). At low doses, the (+)-TCP isomer was
more active in alleviating motor symptoms than the (-)-TCP
isomer, which was explained by more potent MAO inhibition
(Reynolds et al., 1981). Comedication of fixed combinations
of levodopa with decarboxylase inhibitors is possible with
TCP. However, because the selective MAO inhibitors selegiline
and rasagiline can be administered without tyramine restric-
tions, TCP is not recommended for the treatment of Parkin-
son's disease. Finally, although depression has been
successfully treated with TCP in two patients with Alzhei-
mer's dementia, a preliminary study in 7 non-depressed
patients with Alzheimer's dementia had a disappointing out-
come (Jenike, 1985; Tariot et al., 1988).
722
4. Practice of tranylcypromine treatment
4.1. Therapeutic doses
According to the amine hypothesis, increased serotonin and
norepinephrine levels induce changes in neuroplasticity
related to improvement in depression as explained in para-
graph 3.3 of part I. Increased dopamine may add to this target
because dopaminergic hypofrontality was found in negative
schizophrenia, which shares some characteristics with depres-
sion (Da Silva et al., 2008), and decreased dopamine is
discussed in bipolar depression (Berk et al., 2007). Enhanced
phenylethylamine, which is known as an “endogenous amphe-
tamine”, and reduced oxidative stress may also explain some
aspects of the antidepressant activity of TCP (Bortolato et al.,
2008). This basic activity as a MAO inhibitor is achieved with
doses of 10–20 mg/day TCP in most patients. Moreover, the
data of TCP neurobiochemistry (paragraph 3.1 of part I) and
pharmacokinetics together with the finding that TCP levels in
brain were 3-fold higher than in plasma (paragraph 3.4 of part
I) indicate that norepinephrine reuptake inhibition contri-
butes to TCP pharmacology at plasma levels of more than 40
ng/ml, which can be achieved at doses of 40–60 mg/day. As a
third aminergic mechanism, the amphetamine-like dopamine
releasing activity of TCP is very unlikely to occur at these
doses. However, it may be relevant for some patients who
already have high plasma concentrations at low dose and who
are treated with 100 mg/day TCP as in some controlled
clinical trials (Birkenhäger et al., 2004; Freyhan et al.,
1960; Nolen et al. 1985, 1993) or over 100 mg/day according
to a concept of high-dose treatment (Amsterdam and
Berwisch, 1989; Gutze and Baxter, 1987; Pearlman, 1987;
Robinson, 1983; Schmauss, 1996). It is estimated that at least
400 ng/ml TCP in plasma is needed for dopamine releasing
activity in the CNS. In a recent dose escalation study of TRD,
7 of 28 patients (25%) remitted with o 60 mg/day TCP and
6 of the remaining 19 patients (32%) in a high-dose treatment
with 105 7 20 mg/day TCP (mean 7 standard deviation).
Two patients refused high-dose treatment (Stewart et al.,
2014). Unfortunately, no controlled dose finding studies have
been conducted for TCP to date and no data are available for
high doses on the long term. Of the controlled studies already
discussed, approximately one third each used low doses of
o 30 mg/day, medium doses of 30–60 mg/day, and higher
doses of up to 100 mg/day (Table 2); however, an analysis
with respect to dose is complicated by the heterogeneity of
studies. A previous review concluded that optimal response
appears in patients who can tolerate 40–60 mg TCP, which is
also the maximum dose according to recent prescribing
information of marketed TCP drug preparations for patients
who can be closely supervised (Thase et al., 1995). It is
therefore advised to titrate TCP dose with respect to
therapeutic effect and tolerability to a maximum dose of
60 mg/day in inpatients.
4.2. Adverse effects
A typical profile of adverse effects of 30 to 60 mg/day TCP
(n = 63) compared with nortriptyline (n = 61) and placebo
(n = 59) over four weeks of treatment in a randomized
R. Ricken et al.
Figure 4 Adverse effects of tranylcypromine (n = 63 patients)
in a placebo (n = 59) and nortriptyline (n = 61) controlled,
randomized, double-blind, short-term trial with intensive study
of adverse effects and including mild-to-moderate severity (sig-
nificant differences of TCP vs. nortriptyline for dizziness (p
o 0.05), insomnia (p o 0.01) and overexcitement (p o 0.05)
and TCP vs. placebo for dizziness, insomnia and dry mouth
(p o 0.01); 4.5 adverse effects per patient for TCP, 4.8 nortripty-
line and 2.3 placebo (nonsignificant)) (White et al., 1984).
controlled trial is shown in Figure 4. Dizziness, sleeping
disorders, and dry mouth were noted at least once in over
50% of patients through a weekly questionnaire, including
reactions of minimal or low severity and without regard to
causality (White et al., 1984). Dizziness was related to
orthostatic hypotension in the majority of patients and, as
described in similar studies, is the main reason of intoler-
ance to TCP and study drop-out. Higher percentages of
insomnia and overexcitement sharply differentiated TCP
from the TCA. Overexcitement included objective signs of
motor hyperactivity and subjective mental complaints. On
the other hand, patients with nortriptyline suffered more
often from anticholinergic effects such as dry mouth,
constipation, and blurred vision. However, dry mouth was
still high in patients receiving TCP treatment despite the
fact that TCP displays no anticholinergic activity. This is
explained by a specific norepinephrinergic increase in
sympathetic activity of salivary glands due to TCP, which
decompensates the sympathetic-parasympathetic balance
and may therefore mimic a peripheral anticholinergic reac-
tion. Since this mechanism is excluded for central antic-
holinergic effects, confusion was found at placebo level only
for TCP. In a study design focusing solely on medically
significant adverse effects, a somewhat different profile
and lower frequency of adverse effects were found for a
similar dose of TCP: 17% orthostatic hypotension (passing
out, falling), 7% hypomania, 5% paresthesias, and 2%
hypertensive reactions, confusion, urinary retention, sexual
function disorders, and rash. No correlation was observed
between adverse effects, patients below the age of 65, and
sex (Rabkin et al., 1984). Other controlled studies con-
firmed this profile of the most frequent adverse effects and
identified additional less frequent effects in TCP patients,
such as edema, anorexia/loss of appetite, increased appe-
tite, leg cramps/muscle pain, hyperreflexia, diarrhea, sen-
sation of cold, tinnitus, and chest pain (Bartholomew, 1962;
Birkenhäger et al., 2004; Gottfries, 1963; Heinze et al.,
Depression in the perspective of a MAO inhibitor 723

1993; O'Brien et al., 1993; Nolen et al., 1985, 1988; Razani

et al., 1983; Volz et al., 1994a).
No weight gain was found in randomized controlled trials
of TCP (Razani et al., 1983; Volz et al., 1994a) and was of
little relevance for TCP in post-marketing surveillance
studies in contrast to, for example, phenelzine (Cantu and
Korek, 1988; Rabkin et al., 1984). A recent review found
phenelzine, but not TCP, among antidepressants associated
with a greater risk of hepatotoxicity (Voican et al., 2014). In
addition, there are no reports of increased bleeding with
TCP to date. The mean increase in QTc interval was only
4.2 ms (p40.05) with TCP in psychiatric patients, which is
below an accepted threshold of a clinically relevant QTc
increase of 5 ms. In contrast, 12.5 ms (p = 0.01) were found
for amitriptyline as positive control (White et al., 1983).
Figure 5 Adverse effects of TCAs (n = 128 patients), SSRIs
The ECG also did not change in a controlled study of 46 TCP
(n = 30), MAO inhibitors (n = 36, 61% tranylcypromine) and
patients (Volz et al., 1994a). Surprisingly, high blood
atypical antidepressants (n = 14, 71% bupropion) in an open,
pressure was not important in the majority of studies. This
non-interventional, long-term trial with intensive study of
is explained by three forms of hypertension that are all
adverse effects and including mild to moderate severity (mean
unlikely to occur or to be detected during regular TCP
number of adverse effects per visit = 2.6), comparison tranyl-
treatment: (i) an early-onset hypertensive activity of TCP,
cypromine vs. SSRIs: sedation and headache (p o 0.01 each),
(ii) a late-onset hypertensive activity of TCP, and (iii) the
dry mouth, anxiety, nausea and sweating (p o 0.001 each),
well-known hypertensive reaction resulting from tyramine
61.5%, 16.4%, 37.4% and 17.5% of patients with treatment of
by violations of the tyramine-restricted diet. Since the
TCAs, SSRIs, tranylcypromine and bupropion, respectively,
early-onset hypertensive activity of TCP is mild and lasts
received lithium augmentation (Mittmann et al., 1999).
for only one to two hours after ingestion, it is often
overlooked in most cases or noticed as palpations. The
inhibitor which may be translated to a nocebo effect for
late-onset spontaneous form is very rare and the tyramine
TCP (McGrath et al., 2006). An indirect comparison of
reaction can be avoided by dietary restrictions (Keck et al.,
adverse effects observed in clinical studies of antidepres-
1991; Taylor et al., 2005).
sant drugs resulted in codification of the strength of the
Sufficient data are currently lacking on the direct com-
adverse effects (Bauer et al., 2013) (Table 4). Although the
parison of adverse effects of TCP with SSRIs, SSNRIs, and
selection of adverse effects was not comprehensive (e.g.,
other antidepressant drugs introduced after 1990. Although
lacking central anticholinergic, cardiac conduction, and
TCP is not an alternative to these drugs as a first-line
hemostasis effects) and the evaluation of strength was only
treatment, this comparison is important in a theoretical
an approximation, the sum score of the most relevant
perspective as well as in practice when it is imperative to
adverse effects may be calculated as a measure of the
make decisions at the right time of a TCP trial after multiple
mean adverse effect burden. Taken together, data suggest
SSRIs or SSNRIs are used. A long-term open study in out-
that TCP has some advantages over TCAs and exhibits no
patients that assessed TCAs (n = 128), SSRIs (n = 30), MAO
disadvantages compared to SSRIs and SSNRIs as the most
inhibitors (TCP: n = 22, phenelzine: n = 8, moclobemide:
established antidepressants. In practice, the evaluation of
n = 6), and atypical antidepressants (bupropion: n = 10,
the individual risk and treatment situation of a patient
trazodone: n = 3, nefazodone: n = 1) may therefore be
taken into account for a possible trial of TCP may also
used as an estimate. Adverse effects were observed in 85%
strongly consider the adverse effect profile in Table 4.
of visits for TCAs, 71% for SSRIs, 67% for MAO inhibitors, and
66% for atypical antidepressants. Most prominent differ-
ences of TCP and SSRIs in a profile of frequent adverse 4.3. Management of frequent adverse effects
effects (Figure 5) are a higher incidence of dry mouth and a
lower incidence of sedation, headache, anxiety, nausea, The pathophysiological mechanism of orthostatic dysregula-
and sweating for TCP (Mittmann et al., 1999). The absence tion during TCP treatment is not known. Accumulation of
of overexcitement and insomnia for TCP compared to the false neurotransmitters such as octopamine in peripheral
study described above (White et al., 1984) can be explained nerve terminals (Cockhill and Remick, 1987), a direct
by the two year treatment duration. These adverse effects interaction of TCP with postsynaptic alpha-adrenergic
may therefore vanish after long-term treatment or could receptors (Keck et al., 1991), and central and/or peripheral
lead to discontinuation of TCP. A controlled study according norepinephrine reuptake inhibition (Krishnan, 2007;
to the STAR*D protocol compared TCP with a combination of Schlessinger et al., 2011) have been discussed. To cope
venlafaxine and mirtazapine. There were no significant with this frequent adverse effect, correction of contributing
differences in frequency, intensity, or burden of adverse factors found in the patient's anamnesis, education of
effects or in the frequency of serious adverse events. The patients, increased fluids, exercise, temporary use of
discontinuation rate for patients receiving TCP due to side elastic support stockings, NaCl supplementation, caffeine,
effects was double the discontinuation rate of patients dihydroergotamine, direct sympathomimetics (i.e., mido-
receiving the combination, however, in an environment that drine and etilefrin), and fludrocortisone have been recom-
stated explicitly to be “uncomfortable” with the MAO mended (Cockhill and Remick, 1987; Cole and Bodkin, 2002;
724 R. Ricken et al.

Table 4 Comparison of TCP with other antidepressant drugs according to a codification of adverse effect strength with the
categories + + + (high/strong), + + (moderate), + (low/mild), and – (very low/none), WFSBP-guideline for biological
treatment of unipolar depressive disorders (Bauer et al., 2013).

Antidepressant Drug group Adverse effects strength codification Sum of

+codes
Anti- Nausea/ Sedation Insomnia/ Sexual dys- Ortho- Weight
cholinergica Gastrointestinal Agitation function static gain
hypo-
tension

Tranylcypromine irMAO-A/B + + ++ + ++ 7
Phenelzine inhibitor + + + ++ ++ ++ + 10
Moclobemide rMAO-A + + + 3
inhibitor
Amitriptyline TCA +++ +++ + +++ +++ 13
Nortriptyline + + + + + + 6
Imipramine ++ + ++ + ++ ++ 10
Doxepine +++ +++ – ++ +++ ++ 13

Citalopram SSRI ++ ++ ++ 6
Sertraline ++ ++ ++ 6
Paroxetine + ++ ++ ++ + 8
Venlafaxine SSNRI ++ ++ ++ 6
Bupropion SNDRI + + + 3
Mirtazapine NSSA ++ + ++ 5

irMAO-A/B inhibitor irreversible monoamine oxidase A/B inhibitor, rMAO-A inhibitor reversible monoamine oxidase A inhibitor, TCA
tricyclic antidepressant, SSRI selective serotonin reuptake inhibitor, SSNRI selective serotonin norepinephrine reuptake inhibitor,
SNDRI selective norepinephrine dopamine reuptake inhibitor, NSSA norepinephrinergic and specific serotoninergic antidepressant.
a
symptoms commonly caused by muscarinic receptor blockade including dry mouth, sweating, blurred vision, constipation and
urinary retention.

Feinberg, 2004; Rabkin et al., 1985). It should be noted,
however, that long-term dihydroergotamine (organ fibrosis),
direct sympathomimetics (hypertensive reaction), and long-
term fludrocortisone (steroid-related adverse effects) esca-
late adverse effect management with their own risks. Some
authors have even described the safety and efficacy of a
very controlled application of the indirect sympathomi-
metics d-amphetamine and methylphenidate, which are
strictly contraindicated with TCP (Ayd, 1973; Cole and
Bodkin, 2002; Feinberg, 2004). Failure and adverse effects
of these treatments have to be considered and dose
adjustment of TCP may be needed instead of that. Dividing
doses may also be considered since it was found that
increased peak plasma concentrations correlated with
orthostatic hypotension (Mallinger et al., 1986).
Sleep disorders together with possible secondary drowsiness
the following afternoon have been treated with benzodiaze-
pines in controlled trials (e.g., Birkenhäger et al., 2004; O'Brien
et al., 1993) and low-dose trazodone in two open studies
(Jacobsen, 1990; Nierenberg and Keck, 1989). Very little data
are currently available for benzodiazepine-like drugs, such as
zopiclone, together with TCP (Adli et al., 2008); however, no
interactions have been spontaneously reported. Based on
experience with chlorpromazine (Bucci, 1987) and olanzapine
(Roesch-Ely et al., 2011), low doses of sedative low potency or
second generation antipsychotics may be another option for
insomnia due to TCP in depressed patients. These drugs may
also relieve patients from TCP-related overexcitement. Taking
the last dose of TCP not later than 3 or 4 p.m. can be tried to
reduce the risk of insomnia, but this remains a controversial
issue (Cole and Bodkin, 2002; Jenike, 1984; Nolen et al., 1988).
Direct parasympathomimetics, such as bethanechol, have been
recommended in the literature for dry mouth (Cole and Bodkin,
2002). Pilocarpine drug products are also available for this
indication, but an interaction with TCP through CYP2A6-
dependent metabolism is possible. The own early-onset hyper-
tensive activity of TCP, which may occur frequently, rarely
reaches symptomatic levels and has been successfully treated
by dividing doses or with calcium channel blockers or beta-
blockers (Stewart et al., 2014; Taylor et al., 2005).
4.4. Risk of drug-drug interactions
The risk of pharmacokinetic drug interactions in the direc-
tion from TCP to other drugs is low as found in paragraph
3.2 of part I of the review. Insufficient data is available to
evaluate the risk of pharmacokinetic drug interactions in
the direction from other drugs to TCP (paragraph 3.4 of
part I).
Concerning pharmacodynamic drug interactions, as also
reviewed in part I (paragraph 3.5), safe treatment with TCP
first of all requires the prevention of two principle mechan-
isms of drug interaction: (i) serotonergic activation by
Depression in the perspective of a MAO inhibitor
serotonin reuptake inhibitors (e.g. SSRIs, SSNRIs) or seroto-
nin precursors, and (ii) norepinephrinergic activation by
indirect sympathomimetics (e.g. ephedrine, phenylpropa-
nolamine). Norepinephrine reuptake inhibition does not
represent a substantial risk (Gillman, 2007; Schmauss
et al., 1988). Serotonergic activation by serotonin release
is of low practical relevance because most indirect sym-
pathomimetic drugs preferentially release norepinephrine,
and only amphetamine may additionally release serotonin
(Gillman, 2006).
4.5. Risk of food interaction of tranylcypromine
with tyramine
A very special property of TCP is the risk of food interaction
with tyramine and other biogenic amines found in some
foods, such as aged cheese, aged or cured meat and fish,
highly concentrated yeast extract products, soy sauce,
sauerkraut, and alcoholic beverages. The pharmacology of
this interaction has already been summarized in paragraph
3.6 of part I of the review. Therefore, the fundamental
requirement of TCP treatment is a mandatory tyramine-
restricted diet. Lists of foods to be avoided have been
improved recently by a critical reappraisal of old clinical
and chemical-analytical data as well as reference to modern
methods of manufacture and storage of food. In doing so,
modern food, including normal servings of bottled/canned
beer, wine, distilled spirits, and chocolate are now regarded
as less likely to have high tyramine content by some
authors. It has also been discussed that the effort needed
to maintain a tyramine-restricted diet may have been
exaggerated in the perception of some doctors and
patients, thus leading to underuse of TCP (Flockhart,
2012; Gardner et al., 1996; McCabe-Sellers et al., 2006).
In organizational routine, 88% of patients and 94% of
caregivers evaluated tyramine-restricted diet as simple or
well-manageable (Adli et al., 2008).
The incidence of hypertensive reactions after consump-
tion of tyramine-rich food in patients receiving an MAO
inhibitor was approximately 8% prior to the introduction of
dietary restrictions (Blackwell et al., 1967) and decreased
to approximately 1–2% in the 1980s (Robinson and Kurtz,
1987). For example, despite information on the necessary
diet, one of 41 patients on a TCP study deliberately violated
the restrictions by eating cheese and suffered from a
moderately severe reaction without sequelae (Rabkin
et al., 1985). It is interesting that an incidence of 6.6% of
hypertensive reactions in outpatients treated with TCP and
phenelzine (12 of 182 during two years, including one severe
reaction) decreased to zero during the following two years
after incorporation of more vigorous and explicit warnings
(Harrison et al., 1989). Concerning the most severe cases
(i.e., organ damage and death), a review of data from the
1970s estimated the risk of death to be 0.007% after
inclusion of suspicious cases without confirmation of a
causal relationship to TCP (Pare, 1985). Another retro-
spective study published in the 1970s found 50 cases of
severe cerebrovascular complications (0.0014%), including
15 deaths (0.0004%), in 3.5 million patients treated with
TCP, also without confirmation of a causal relationship
(Baldessarini, 1996). In addition, a German study reported
725
6 cases of intracranial hemorrhage in 102,000 TCP patients
(0.006%) (Haase and Buhr, 1973). No cases of a severe
tyramine reaction were found in a more recent analysis of
TCP treatment in a retrospective chart review of 348
patients older than 65 years (Shulman et al., 2009). It is
of interest in this respect that SSRIs were also found to bear
a very low risk of intracranial hemorrhage because of
inhibition of the platelet serotonin reuptake transporter
(Hackam and Mrkobrada, 2012). The risk of tyramine inter-
action determines for the main part the benefit-risk-ratio
and place in therapy of TCP as discussed in more detail in
paragraph 5.
4.6. Risk of drug dependence and abuse
A recent review identified 18 published cases of withdrawal
syndrome, including 10 patients with delirium, after TCP
dependence/abuse at doses of 120 to 600 mg/day. Previous
or current substance dependence/abuse from psychotropic
drugs other than TCP was identified in 14 of these patients
(78%). Discontinuation phenomena without dependence/
abuse were found in 7 reports, including three patients
with delirium, at doses of 20 to 140 mg/day (Gahr et al.,
2013). The amphetamine-like activity of TCP together with
favorable pharmacokinetics (fast absorption, short half-life)
is regarded as the mechanistic basis of TCP dependence/
abuse. As for amphetamine anorectic medications (O’Brian,
1995), however, the risk seems to be limited to rare cases.
In conclusion, TCP should not be prescribed to patients with
a history of substance dependence/abuse and cluster B
personality traits (borderline, narcistic, histrionic), and a
slow incremental dose reduction is advised for discontinua-
tion of TCP. High-dose treatment with TCP as reported in
very rare cases (see paragraph 4.1) may be a critical
approach with respect to the risk of dependence and abuse.
4.7. Tranylcypromine in elderly patients
MAO-B activity is well-known to be increased with age (Mahy
et al., 2000; Robinson et al., 1972; White et al., 1980b),
which may provide a pathophysiological rationale for the use
of TCP in the treatment of depression of older patients
(Jenike, 1984, 1985) as well as neurodegenerative disorders
(Baker et al., 2007; Fahn and Chouinard, 1998). Moreover,
the risk of some adverse effects and drug interactions
relevant for elderly patients and known for other antide-
pressants are minimal or absent for TCP, such as central
anticholinergic effects, direct peripheral anticholinergic
reactions, ECG changes, increased bleeding, and pharmaco-
kinetic interactions. There is therefore no principal restric-
tion for TCP treatment with regard to age of patients in the
absence of contraindications that may be more often
encountered in the elderly, such as severe cardiovascular
disorders, high blood pressure, hepatic and severe renal
insufficiency, or cerebrovascular disorders. In addition, cog-
nitive impairment more often encountered in older patients
may detract from the mandatory tyramine-restricted diet.
Sustained trouble with severe orthostatic hypotension should
be added as a reason for the withdrawal of TCP and general
caution is advised because older patients have less compen-
satory reserve to cope with any serious adverse reaction.
726
Very few patients over the age of 65 have been included
in controlled studies of TCP. However, successful treatment
of old patients with TCP has been described in several case
report series (Ashford and Ford, 1979; Harms et al., 2000;
Jenike, 1984, 1985; Lieb and Collins, 1978; Oostervink
et al., 2003). A non-interventional clinical study exclusively
in patients over the age of 65 years included 22 patients
treated with TCP for two years (Mittmann et al., 1999).
Moreover, a recent observational cohort study in 348
patients over the age of 65 years found the use of TCP to
be safe (Shulman et al., 2009). Another non-interventional
study included 27 patients over the age of 70 years and also
found no increase in the frequency of adverse effects in
patients greater than 65 years compared to patients
between the ages of 40 to 60 years who had all been
screened for active coronary or cerebrovascular insuffi-
ciency. The author of this study concluded in 1978 that
“the admonition that TCP should not be used in patients
over 65 should be withdrawn” (Lesse, 1978) and other
authors concluded in 2009 that TCP and phenelzine should
be used more for atypical and treatment-resistant depres-
sion of older patients (Shulman et al., 2009).
4.8. Tranylcypromine and anesthesia/analgesia
New studies have provided evidence that the use of general
and local anesthesia in a controlled manner and with careful
evaluation of the individual risk may be safe in psychiatric
patients without discontinuation of TCP. The high psychiatric
risk of discontinuation of TCP in TRD is likely to outweigh the
increased yet manageable perioperative risk from continuing
TCP during anesthesia/analgesia (El-Ganzouri et al., 1985;
Krings-Ernst et al., 2013; Pass and Simpson, 2004; Stack
et al., 1988; Van Haelst et al., 2012). Controlling factors
include the exclusion of several drugs used in anesthesia/
analgesia (e.g., indirect sympathomimetics for hypotension
substituted by direct sympathomimetics, serotonergic opioids
substituted by non-serotonergic opioids), exclusion of cardiac
surgery or other conditions that constitute an independent
contraindication of TCP, and maintenance of sympathetic
homeostasis through the use of sufficient preoperative anti-
anxiety medications and perioperative avoidance of pain,
hypoxia, hypercapnia, and hypotension. Maintenance of
sympathetic homeostasis may also require avoidance of
short-term discontinuation of TCP prior to anesthesia/
analgesia because complete sympathetic readjustment actu-
ally requires more than two weeks. A previous report showed
that discontinuation of TCP even three weeks before surgery
still retained some perioperative risk in a multi-morbid 79
year-old patient (Sprung et al., 1996). Therefore, a general
endorsement of MAO inhibitor discontinuation before
anesthesia/analgesia has been regarded as challenging or
even inadequate (Krings-Ernst et al., 2013; Pass and Simpson,
2004; Stack et al., 1988; Van Haelst et al., 2012). Other
authors still prefer MAO inhibitor discontinuation of two
weeks (Huyse et al., 2006), which was adopted in recent
anesthesiology guidelines; however, there is minimal evi-
dence to support this recommendation to date (De Hert
et al., 2011). Taking into account the special properties of a
drug (e.g., TCP being less prone to pharmacokinetic inter-
actions than phenelzine) may also help in the difficult
R. Ricken et al.
decision on discontinuation or continuation of TCP during
the use of anesthesia/analgesia.
4.9. Tranylcypromine and electroconvulsive
therapy (ECT)
The administration of ECT and 20 mg/day TCP when started
together was found to be safe and had similar efficacy as
ECT with placebo in a controlled trial over four weeks
(Monaco and Delaplaine, 1964). Thousands of patients
thereafter received this combination as mentioned in a
report of 1975 (Sargant, 1975). TCP in combination with ECT
was also safe in 13 patients compared to a control group of
45 patients receiving ECT alone in a report from 1985
(El-Ganzouri et al., 1985). According to more recent data
of 5 patients, multiple ECT sessions were safe during
treatment with higher doses of up to 80 mg/day TCP and
depression resolved after insufficient improvement or wor-
sening with TCP alone (Dolenc et al., 2004; Ribeiro et al.,
2008). Therefore, it can be concluded that ECT augmenta-
tion may be a suitable approach for patients who do not
respond to TCP alone.
5. The benefit-risk ratio of tranylcypromine
and place in therapy
Since it is well-accepted that the efficacy of antidepressants
is approximately equal in controlled trials, only the risks
need to be discussed for a comparison of benefit-risk ratio.
The risk of TCP is mainly due to a potential for a tyramine
hypertensive reaction, and therefore TCP has considerably
higher risk than TCAs, SSNRIs, or SSRIs. On the other hand,
the risk of a chronic course of depression is increased with a
higher number of failed antidepressant trials (Bauer et al.,
2013; Mathys and Mitchell, 2011), and suicidality reached
50–62% in patients with treatment-resistant depression
(TRD) (Price et al., 2009). Thus, the risk of the disease is
considerably higher in TRD and it may compensate for the
increased risk of the drug at a certain stage of TRD.
Therefore, it is advised not to delay or even omit an
established treatment that includes a completely new
pharmacological approach, such as MAO inhibition. The
advantages of TCP should also be considered, such as low
risk of pharmacokinetic interactions, low risk of weight
gain, and no central anticholinergic effects. In comparison
to lithium augmentation, TCP treatment avoids polyphar-
macy, long-term nephrotoxicity, and plasma level assays.
In a synthesis of this evaluation, irreversible MAO inhibitors
have been incorporated as the 4th treatment step in algo-
rithms of antidepressant treatment after administration of
two other antidepressants and lithium augmentation (Adli
et al., 2002; Bauer et al., 2009; Kennedy et al., 2001; Spijker
and Nolen, 2010; Trivedi et al., 2006). One algorithm even
recommends earlier trials with MAO inhibitors in case of
atypical depression (Spijker and Nolen, 2010). Superiority of
treatment according to such algorithms was found compared
with treatment as usual (Bauer et al., 2009; Trivedi et al.,
2006) and systematic treatments are also recommended in
recent guidelines and state of the art articles (Bauer et al.,
2013; Kupfer, 2005). Moreover, international guidelines, such
as in the American Psychiatric Association (APA) and World
Depression in the perspective of a MAO inhibitor
Federation of Societies of Biological Psychiatry (WFSBP)
guidelines, include irreversible MAO inhibitors as a third-line
antidepressant (Thase, 2012).
6. Conclusions and future development of
tranylcypromine
Recent scientific evaluation continues to support the use of
TCP in TRD with atypical depression as a domain of TCP use.
Bipolar and anergic depression may also be added because
they are likely to be related to atypical depression in many
patients and since TCP showed positive results in these
conditions. Although no differential pharmacotherapy of
depression is available based on biological correlates, recent
studies of an association of increased MAO activity with traits
and severity of depression, together with clinical experience,
point to the existence of a subset of patients who may
particularly benefit from MAO inhibitor treatment. Clinical
and pathophysiological scenarios have been hypothesized
that utilize the MAO inhibitor in an individualized treatment
plan. The identification of these “MAO inhibitor patients”
who would likely benefit from MAO inhibition is a clinically
intuitive approach today. Psychiatrists should therefore
become familiar with TCP treatment approaches and evalu-
ate the benefit-risk-ratio in each case (Schwartz, 2013).
Clinical practice has surpassed the scientific development
of TCP in many areas. For example, no controlled studies
have been conducted to date to compare the efficacy of
SSRIs/SSNRIs with TCP because they are not first-line
treatment competitors due to safety reasons. However, this
represents a theoretical gap. A switch study to TCP while
continuing the comparator antidepressant, studies of PET
imaging of MAO activity in TCP patients, and clinical studies
addressing neuroprotection with TCP are all studies that
should be considered in the future. Moreover, taking into
account the therapeutic potential of TCP, sufficient MAO
inhibition in the CNS without MAO inhibition in liver and gut,
to overcome tyramine restricted diet, still appears to be a
basic research target. The authors of this review are
currently conducting a comparative study of TCP and
lithium augmentation in TRD patients (TraveL study, tranyl-
cypromine versus lithium augmentation). Finally, very inter-
esting research with TCP has been growing outside the area
of neuropsychopharmacology during the past decade, and
these studies of TCP and TCP derivatives as LSD1 inhibitors
may open new therapeutic approaches.
Role of funding source
Aristo Pharma did add to the preparation of the manuscript only in
form of intellectual support.
Contributors
Roland Ricken, Mazda Adli and Sven Ulrich established the concep-
tion of the manuscript. Roland Ricken wrote the first version of the
manuscript. Sven Ulrich and Roland Ricken undertook and Peter
Schlattmann reviewed the statistical analysis. All authors contrib-
uted to and have approved the final manuscript.
727
Conflict of interest
Roland Ricken has received a research grant from Aristo. Sven Ulrich
is working in the pharmaceutical company Aristo Pharma GmbH
marketing a tranylcypromine drug product. Peter Schlattmann
reports no conflicts of interest. Mazda Adli has received speaker
honoraria from Deutsche Bank, HRMForum, Aristo, Merz, Gilead, ViiV,
MSD, Berlin Chemie, BMS, mytomorrows, Servier and Lundbeck,
reimbursement of fees and of travel expenses for scientific meetings
from Lundbeck, Aristo and Servier and research grants from Servier
and Lundbeck.
Acknowledgements
Peter Schlattmann received grants from the German Ministry of
Education and Research (BMBF) for meta-analyses as part of the
joint program "Clinical trials" of the BMBF and the German Science
Foundation (DFG), and from the European Union.
References
Adli, M., Berghöfer, A., Linden, M., Helmchen, H., Müller-
Oerlinghausen, B., Mackert, A., Stamm, T., Bauer, M., 2002.
Effectiveness and feasibility of a standardized stepwise drug
treatment regimen algorithm for inpatients with depressive
disorders: results of a 2-year observational algorithm study. J.
Clin. Psychiatry 63, 782–790.
Adli, M., Pilhatsch, M., Bauer, M., Köberle, U., Ricken, R., Janssen,
G., Ulrich, S., Bschor, T., 2008. Safety of high-intensity treat-
ment with the irreversible monoamine oxidase inhibitor tranyl-
cypromine in patients with treatment-resistant depression.
Pharmacopsychiatry 41, 252–257.
Akiskal, H.S., Benazzi, F., 2005. Atypical depression: a variant of
bipolar II or a bridge between unipolar and bipolar II? J. Affect.
Disord. 84, 209–217.
American Psychiatric Association (APA), 2010. Practice Guideline for
the Treatment of Patients With Major Depressive Disorder, Third
Edition. Retrieved from: 〈http://psychiatryonline.org/guide
lines〉 (March 16th 2015).
Amsterdam, J.D., Berwisch, N.J., 1989. High dose tranylcypromine
therapy for refractory depression. Pharmacopsychiatry 22,
21–25.
Ashford, J.W., Ford, C.V., 1979. Use of MAO-inhibitors in elderly
patients. Am. J. Psychiatry 136, 1466–1467.
Atkinson, R.M., Ditman, K.S., 1965. Tranylcypromine: a review.
Clin. Pharmacol. Ther. 6, 631–655.
Ayd Jr., F.J., 1973. Doxepin with other drugs. South Med. J. 66,
465–471.
Baker, G.B., Sowa, B., Todd, K.G., 2007. Amine oxidases and their
inhibitors: what can they tell us about neuroprotection and the
development of drugs for neuropsychiatric disorders? J. Psychia-
try Neurosci. 32, 313–315.
Baldessarini, R.J., 1996. Drugs and the treatment of psychiatric
disorders. In: Hardman, J.G., Limbird, L.E., Molinoff, P.B.,
Ruddon, R.W., Gilman, A.G. (Eds.), The Pharmacological Basis
of Therapeutics 9th ed. McGraw-Hill, New York, pp. 431–459.
Bandelow, B., Zohar, J., Hollander, E., Kasper, S., Möller, H.J.,
2008. WFSBP Task Force on Treatment Guidelines for Anxiety,
Obsessive-Compulsive and Post-Traumatic Stress Disoders. World
Federation of Societies of Biological Psychiatry (WFSBP) guide-
lines for the pharmacological treatment of anxiety, obsessive-
compulsive and post-traumatic stress disorders - first revision.
World J. Biol. Psychiatry 9, 248–312.
Barsa, J.A., Saunders, J.C., 1962. Tranylcypromine in the treatment
of chronic schizophrenics. Am. J. Psychiatry 118, 933–934.
728
Bartholomew, A.A., 1962. An evaluation of tranylcypromine ("Par-
nate") in the treatment of depression. Med. J. Aust. 49, 655–662.
Bauer, M., Pfennig, A., Linden, M., Smolka, M.N., Neu, P., Adli, M.,
2009. Efficacy of an algorithm-guided treatment compared with
treatment as usual: a randomized, controlled study of inpatients
with depression. J. Clin. Psychopharmacol. 29, 327–333.
Bauer, M., Pfennig, A., Severus, E., Whybrow, P.C., Angst, J.,
Möller, H.J., 2013. World Federation of Societies of Biological
Psychiatry (WFSBP) guidelines for biological treatment of uni-
polar depressive disorders, part 1: update 2013 on the acute and
continuation treatment of unipolar depressive disorders. World
J. Biol. Psychiatry 14, 334–385.
Berk, M., Dodd, S., Kauer-Sant'anna, M., Malhi, G.S., Bourin, M.,
Kapczinski, F., Norman, T., 2007. Dopamine dysregulation syn-
drome: implications for a dopamine hypothesis of bipolar
disorder. Acta Psychiatr. Scand. 434S, 41–49.
Birkenhäger, T.K., van den Broek, W.W., Mulder, P.G., Bruijn, J.A.,
Moleman, P., 2004. Efficacy and tolerability of tranylcypromine
versus phenelzine: a double-blind study in antidepressant-
refractory depressed inpatients. J. Clin. Psychiatry 65, 1505–1510.
Blackwell, B., Marley, E., Price, J., Taylor, D., 1967. Hypertensive
interactions between monoamine oxidase inhibitors and food-
stuffs. Br. J. Psychiatry 113, 349–365.
Blanco, C., Bragdon, L.B., Schneier, F.R., Liebowitz, M.R., 2013.
The evidence-based pharmacotherapy of social anxiety disorder.
Int. J. Neuropsychopharmacol. 16, 235–249.
Boerner, R.F., Luehring, F., 2010. Tranylcypromine for chronic
therapyresistant agoraphobia with panic disorder and recurrent
depressive disorder. Psych. Prax. 37, 350–352.
Bucci, L., 1969. The monoamine oxidase inhibitors: their usefulness
and their safety. Dis. Nerv. Syst. 30, 843–847.
Bucci, L., 1987. Negative symptoms of schizophrenia and mono-
amine oxidase inhibitors. Psychopharmacology 91, 104–108.
Buffaloe, W.J., Sandifer, M.G., 1961. A study of combined therapy
with stelazine and parnate (SKF 385) in chronic anergic schizo-
phrenics. Am. J Psychiatry 117, 1030–1031.
Bortolato, M., Chen, K., Shih, J.C., 2008. Monoamine oxidase
inactivation: from pathophysiology to therapeutics. Adv. Drug
Deliv. Rev. 60, 1527–1533.
Cantu, T.G., Korek, J.S., 1988. Monoamine oxidase inhibitors and
weight gain. Drug Intell. Clin. Pharm. 22, 755–759.
Chiuccariello, L., Houle, S., Miler, L., Cooke, R.G., Rusjan, P.M.,
Rajkowska, G., Levitan, R.D., Kish, S.J., Kolla, N.J., Ou, X.,
Wilson, A.A., Meyer, J.H., 2014. Elevated monoamine oxidase A
binding during major depressive episodes is associated with
greater severity and reversed neurovegetative symptoms. Neu-
ropsychopharmacology 39, 973–980.
Clemons, W.E., Makela, E., Young, J., 2004. Concomitant use of
modafinil and tranylcypromine in a patient with narcolepsy: a
case report. Sleep. Med. 5, 509–511.
Cockhill, L.A., Remick, R.A., 1987. Blood pressure effects of
monoamine oxidase inhibitors – the highs and lows. Can. J.
Psychiatry 32, 803–808.
Cole, J.O., Bodkin, J.A., 2002. MAO inhibitors: an option worth
trying in treatment-resistant cases. Curr. Psychiatry 1, 40–47.
Cowdry, R.W., Gardner, D.L., 1988. Pharmacotherapy of border-
line personality disorder. Alprazolam, carbamazepine, trifluo-
perazine, and tranylcypromine. Arch. Gen. Psychiatry 45,
111–119.
D'Agostino, R.B., Weintraub, M., 1995. Meta-analysis: a method for
synthesizing research. Clin. Pharmacol. Ther. 58, 605–616.
Da Silva, A.F., Figee, M., Vamelsvoort, T., Veltman, D., de Haan, L.,
2008. The revised dopamine hypothesis of schizophrenia: evi-
dence from pharmacological MRI studies with atypical antipsy-
chotic medication. Psychopharmacol. Bull. 41, 121–132.
Deckert, J., Catalano, M., Syagailo, Y.V., Bosi, M., Okladnova, O., Di
Bella, D., et al., 1999. Excess of high activity monoamine
R. Ricken et al.
oxidase A gene promoter alleles in female patients with panic
disorder. Hum. Mol. Genet. 8, 621–624.
De Hert, S., Imberger, G., Carlisle, J., Diemunsch, P., Fritsch, G.,
Moppett, I., Solca, M., Staender, S., Wappler, F., Smith, A.,
2011. Preoperative evaluation of the adult patient undergoing
noncardiac surgery: guidelines from the European Society of
Anaesthesiology. Eur. J. Anaesthesiol. 28, 684–722.
Dilsaver, S.C., Del Medico, VJ, Quadri, A, Jaeckle, RS, 1990.
Pharmacological responsiveness of winter depression. Psycho-
pharmacol. Bull. 26, 303–309.
Dolenc, T.J., Habl, S.S., Barnes, R.D., Rasmussen, K.G., 2004.
Electroconvulsive therapy in patients taking monoamine oxidase
inhibitors. J. ECT 20, 258–261.
El-Ganzouri, A.R., Ivankovich, A.D., Braverman, B., McCarthy, R.,
1985. Monoamine oxidase inhibitors: should they be discontin-
ued preoperatively? Anesth. Analg. 64, 592–596.
Erfurth, A., Schmauss, M., 1993. Monoamine oxidase inhibitors in the
treatment of obsessive-compulsive disorder. Nervenarzt 64, 70–72.
Fahn, S., Chouinard, S., 1998. Experience with tranylcypromine in
early Parkinson´s disease. J. Neural Transm. 52 (S), 49–61.
Feinberg, S.S., 2004. Combining stimulants with monoamine oxi-
dase inhibitors: a review of uses and possible additional indica-
tion. J. Clin. Psychiatry 65, 1520–1524.
Flockhart, D.A., 2012. Dietary restrictions and drug interactions
with monoamine oxidase inhibitors: an update. J. Clin. Psychia-
try 73 (S1), 17–24.
Freyhan, F.A., 1960. The modern treatment of depressive disorders.
Am. J. Psychiatry 116, 1057–1064.
Gahr, M., Schönfeldt-Lecuona, C., Kölle, M.A., Freudenmann, R.W.,
2013. Withdrawal and discontinuation phenomena associated
with tranylcypromine: a systematic review. Pharmacopsychiatry
46, 123–129.
Gardner, D.M., Shulman, K.I., Walker, S.E., Tailor, S.A., 1996. The
making of a user friendly MAOI diet. J. Clin. Psychiatry 57,
99–104.
Gernaat, H.B., Haffmans, P.M., Knegtering, H., Birkenhäger, T.K.,
1995. Tranylcypromine in narcolepsy. Pharmacopsychiatry 28,
98–100.
Gosciniak, H.T., 1997. Switch from tranylcypromine to moclobe-
mide. Psychopharmakotherapy 4, 106.
Gillman, P.K., 2006. A review of serotonin toxicity data: implica-
tions for the mechanisms of antidepressant drug action. Biol.
Psychiatry 59, 1046–1051.
Gillman, P.K., 2007. Tricyclic antidepressant pharmacology and
therapeutic drug interactions updated. Br. J. Pharmacol. 151,
737–748.
Glick, B.S., 1964. Double-blind study of tranylcypromine and
phenelzine in depression. Dis. Nerv. Syst. 25, 617–619.
Gottfries, C.G., 1963. Clinical trial with the monoamino oxidase
inhibitor tranylcypromine on a psychiatric clientele. Acta Psy-
chiat Scand. 39, 463–472.
Grunze, H., Vieta, E., Goodwin, G.M., Bowden, C., Licht, R.W.,
Möller, H.J., Kasper, S., 2010. The World Federation of Societies
of Biological Psychiatry (WFSBP) Guidelines for the Biological
Treatment of Bipolar Disorders: update 2010 on the treatment of
acute bipolar depression. World J. Biol. Psychiatry 11, 81–109.
Gutze, B.H., Baxter jr., L.R., 1987. Refractory depression treated
with high doses of a monoamine oxidase inhibitor. J. Clin.
Psychiatry 48, 31–32.
Haase, H.J., Buhr, H.J., 1973. Investigations on the tolerability of
the antidepressant Jatrosom. Med. Welt 24, 221–224.
Hackam, D.G., Mrkobrada, M., 2012. Selective serotonin reuptake
inhibitors and brain hemorrhage: a meta-analysis. Neurology 79,
1862–1865.
Harms, H.H., de Reus, R., Pootjes, Y.G., Rooze, H.A., 2000.
Successful treatment of an elderly woman after stubborn
resistance. Ned. Tijdschr. Geneeskd. 144, 201–203.
Depression in the perspective of a MAO inhibitor
Harrison, W.M., McGrath, P.J., Steward, J.W., Quitkin, F., 1989.
MAOIs and hypertensive crises: the role of OTC drugs. J. Clin.
Psychiatry 50, 64–65.
Hedberg, D.L., Houck, J.H., Glueck, B.C., 1971. Tranylcypromine-
trifluoperazine combination in the treatment of schizophrenia.
Am. J. Psychiatry 127, 1141–1146.
Heijnen, W.T., De Fruyt, J., Wierdsma, A.I., Sienaert, P., Birkenhä-
ger, T.K., 2015. Efficacy of tranylcypromine in bipolar depres-
sion: a systematic review. J. Clin. Psychopharmacol. 35,
700–705.
Heikkila, R.E., Manzino, L., Cabbat, F.S., Duvoisin, R.C., 1984.
Protection against the dopaminergic neurotoxicity of 1-methyl-
4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase
inhibitors. Nature 311, 467–469.
Heinze, G., Rossel, L., Gabelic, I., Galeano-Munoz, J., Stabl, M.,
Allen, S.R., 1993. Double-blind comparison of moclobemide and
tranylcypromine in depression. Pharmacopsychiatry 26, 240–245.
Himmelhoch, J.M., Fuchs, C.Z., Symons, B.J., 1982. A double-blind
study of tranylcypromine treatment of major anergic depres-
sion. J. Nerv. Ment. Dis. 170, 628–634.
Himmelhoch, J.M., Thase, M.E., Mallinger, A.G., Houck, P., 1991.
Tranylcypromine versus imipramine in anergic bipolar depres-
sion. Am. J. Psychiatry 148, 910–916.
Hordern, A., Somerville, D.M., Krupinski, J., 1962. Does chronic
schizophrenia respond to a combination of a neuroleptic and an
antidepressant? J. Nerv. Ment. Disord. 134, 361–376.
Huyse, F.J., Touw, D.J., van Schijndel, R.S., de Lange, J.J., Slaets, J.P.J.,
2006. Psychotropic drugs and the perioperative period: a proposal for
a guideline in elective surgery. Psychosomatics 47, 8–22.
Jacobsen, F.M., 1990. Low-dose trazodone as a hypnotic in patients
treated with MAOIs and other psychotropics: a pilot study. J.
Clin. Psychiatry 51, 298–302.
Jenike, M.A., 1981. Rapid response of severe obsessive-compulsive
disorder to tranylcypromine. Am. J. Psychiatry 138, 1249–1250.
Jenike, M.A., 1984. The use of monoamine oxidase inhibitors in the
treatment of elderly, depressed patients. J. Am. Geriatr. Soc.
32, 571–575.
Jenike, M.A., 1985. Monoamine oxidase inhibitors as treatment for
depressed patients with primary degenerative dementia (Alz-
heimer's disease). Am. J. Psychiatry 142, 763–764.
Joffe, R.T., 1996. Tranylcypromine in recurrent brief depression:
two case reports. Int. Clin. Psychopharmacol. 11, 287–288.
Keck Jr, P.E., Carter, W.P., Nierenberg, A.A., Cooper, T.B., Potter,
W.Z., Rothschild, A.J., 1991. Acute cardiovascular effects of
tranylcypromine: correlation with plasma drug, metabolite,
norepinephrine, and MHPG levels. J. Clin. Psychiatry 52,
250–254.
Kennedy, S.H., Lam, R.W., Cohen, N.L., Ravindran, A.V., CANMAT
Depression Work Group, 2001. Canadian Network for Mood and
Anxiety Treatments. Clinical guidelines for the treatment of
depressive disorders. IV Medications and other biological treat-
ments. Can. J. Psychiatry 46 (S), 38–57.
Khanna, J.L., Pratts, S., Burdzik, E.G., Chaddha, R.L., 1963. A study
of certain effects of tranylcypromine, a new antidepressant. J.
New Drugs 3, 227–232.
Krings-Ernst, I., Ulrich, S., Adli, M., 2013. Antidepressant treatment
with MAO-inhibitors during general and regional anesthesia: a
review and case report of spinal anesthesia for lower extremity
surgery without discontinuation of tranylcypromine. Int. J. Clin.
Pharmacol. Ther. 51, 763–770.
Krishnan, K.R., 2007. Revisiting monoamine oxidase inhibitors. J.
Clin. Psychiatry 68 (S8), 35–41.
Kruse, W., 1960. Trifluoperazine and tranylcypromine in chronic
refractory schizophrenics. Am. J. Psychiatry 117, 548–549.
Kupfer, D.J., 2005. The pharmacological management of depres-
sion: state of the art. Dialog. Clin. Neurosci. 7, 191–205.
729
Lesse, S., 1978. Tranylcypromine (Parnate) - a study of 1000
patients with severe agitated depressions. Am. J. Psychother.
32, 220–242.
Lieb, J., Collins, C., 1978. Treatment of delusional depression with
tranylcypromine. J. Nerv. Ment. Disord. 166, 805–808.
Mahy, N., Andrés, N., Andrade, C., Saura, J., 2000. Age-related
changes of MAO-A and -B distribution in human and mouse brain.
Neurobiology 8, 47–54.
Mallinger, A.G., Edwards, D.J., Himmelhoch, J.M., et al., 1986.
Pharmacokinetics of tranylcypromine in patients who are
depressed: relationship to cardiovascular effects. Clin. Pharma-
col. Ther. 40, 444–450.
Mallinger, A.G., Frank, E., Thase, M.E., Barwell, M.M., Diazgranados,
N., Luckenbaugh, D.A., Kupfer, D.J., 2009. Revisiting the effective-
ness of standard antidepressants in bipolar disorder: are monoamine
oxidase inhibitors superior? Psychopharmacol. Bull. 42, 64–74.
Mathys, M., Mitchell, B.G., 2011. Targeting treatment-resistant
depression. J. Pharm. Pract. 24, 520–533.
McCabe-Sellers, B.J., Staggs, C.G., Bogle, M.L., 2006. Tyramine in
foods and monoamine oxidase inhibitor drugs: a crossroad where
medicine, nutrition, pharmacy, and food industry converge. J.
Food Compos. Anal. 19 (S), 58–65.
McGrath, P.J., Quitkin, F.M., Harrison, W., Stewart, J.W., 1984.
Treatment of melancholia with tranylcypromine. Am. J. Psy-
chiatry 141, 288–289.
McGrath, P.J., Stewart, J.W., Fava, M., Trivedi, M.H., Wisniewski, S.R.,
Nierenberg, A.A., Thase, M.E., Davis, L., Biggs, M.M., Shores-
Wilson, K., Luther, J.F., Niederehe, G., Warden, D., Rush, A.J.,
2006. Tranylcypromine versus venlafaxine plus mirtazapine follow-
ing three failed antidepressant medication trials for depression: a
STAR*D report. Am. J. Psychiatry 163, 1531–1541.
McGrath, P.J., Stewart, J.W., Harrison, W., Quitkin, F.M., 1987.
Treatment of tricyclic refractory depression with a monoamine
oxidase inhibitor antidepressant. Psychopharmacol. Bull. 23,
169–172.
Mena, A., Heistadt, G., Schiele, B.C., Janecek, J., 1964. A
comparison of tranylcypromine alone with tranylcypromine plus
trifluoperazine in the treatment of chronic outpatients: a double
blind controlled study. J. Neuropsychiatry 5, 542–550.
Mitchell, P.B., Goodwin, G.M., Johnson, G.F., Hirschfeld, R.M.,
2008. Diagnostic guidelines for bipolar depression: a probabil-
istic approach. Bipolar Disord. 10 (1 Pt 2), 144–152.
Mittmann, N., Herrmann, N., Shulman, K.I., Silver, I.L., Busto, U.
E., Borden, E.K., Naranjo, C.A., Shear, N.H., 1999. The effec-
tiveness of antidepressants in elderly depressed outpatients: a
prospective case series study. J. Clin. Psychiatry 60, 690–697.
Monaco, J.T., Delaplaine, R.P., 1964. Tranylcypromine with ECT.
Am. J. Psychiatry 120, 1003.
Naoi, M., Riederer, P., Maruyama, W., 2016. Modulation of mono-
amine oxidase (MAO) expression in neuropsychiatric disorders:
genetic and environmental factors involved in type A MAO
expression. J. Neural Transm. (Vienna) 123, 91–106.
Nardi, A.E., Lopes, F.L., Valença, A.M., Freire, R.C., Nascimento, I.,
Veras, A.B., Mezzasalma, M.A., de-Melo-Neto, V.L., Soares-
Filho, G.L., King, A.L., Grivet, L.O., Rassi, A., Versiani, M.,
2010. Double-blind comparison of 30 and 60 mg tranylcypromine
daily in patients with panic disorder comorbid with social
anxiety disorder. Psychiatry Res. 175, 260–265.
Neyeloff, J.L., Fuchs, S.C., Moreira, L.B., 2012. Meta-analyses and
forest plots using a microsoft excel spreadsheet: step-by-step guide
focusing on descriptive data analysis. BMC Res. Notes 5, 52.
Nierenberg, A.A., Keck Jr., P.E., 1989. Management of monoamine
oxidase inhibitor-associated insomnia with trazodone. J. Clin.
Psychopharmacol. 9, 42–45.
Nolen, W.A., Haffmans, P.M., Bouvy, P.F., Duivenvoorden, H.J.,
1993. Monoamine oxidase inhibitors in resistant major depres-
sion. A double-blind comparison of brofaromine and
730
tranylcypromine in patients resistant to tricyclic antidepres-
sants. J. Affect. Disord. 28, 189–197.
Nolen, W.A., Kupka, R.W., Hellemann, G., Frye, M.A., Altshuler, L.L.,
Leverich, G.S., Suppes, T., Keck Jr, P.E., McElroy, S., Grunze, H.,
Mintz, J., Post, R.M., 2007. Tranylcypromine vs. lamotrigine in the
treatment of refractory bipolar depression: a failed but clinically
useful study. Acta Psychiatr. Scand. 115, 360–365.
Nolen, W.A., van de Putte, J.J., Dijken, W.A., Kamp, J.S., 1985. L-5HTP
in depression resistant to re-uptake inhibitors. An open comparative
study with tranylcypromine. Br. J. Psychiatry 147, 16–22.
Nolen, W.A., van de Putte, J.J., Dijken, W.A., Kamp, J.S.,
Blansjaar, B.A., Kramer, H.J., Haffmans, J., 1988. Treatment
strategy in depression. II. MAO inhibitors in depression resistant
to cyclic antidepressants: two controlled crossover studies with
tranylcypromine versus L-5-hydroxytryptophan and nomifensine.
Acta Psychiatr. Scand. 78, 676–683.
O’Brian, C.P., 1995. Drug addiction and drug abuse. In: Hardman, J.G.,
Limbird, L.E. (Eds.), Goodman and Gilman's. The Pharmacological
Basis of Therapeutics. McGraw-Hill, New York, pp. 557–577.
O'Brien, S., McKeon, P., O'Regan, M., 1993. The efficacy and
tolerability of combined antidepressant treatment in different
depressive subgroups. Br. J. Psychiatry 162, 363–368.
Oostervink, F., Bouvy, P.F., Touw, D.J., 2003. Elderly patients,
classical monoamine oxidase inhibitors and intercurrent somatic
diseases. Ned. Tijdschr. Geneeskd. 147, 1937–1940.
Pae, C.U., Tharwani, H., Marks, D.M., Masand, P.S., Patkar, A.A.,
2009. Atypical depression: a comprehensive review. CNS Drugs
23, 1023–1037.
Pare, C.M., 1985. The present status of monoamine oxidase
inhibitors. Br. J. Psychiatry 146, 576–584.
Pare, C.M., Mack, J.W., 1971. Differentiation of two genetically
specific types of depression by the response to antidepressant
drugs. J. Med. Genet. 8, 306–309.
Parker, G., Roy, K., Mitchell, P., Wilhelm, K., Malhi, G., Hadzi-
Pavlovic, D., 2002. Atypical depression: a reappraisal. Am. J.
Psychiatry 159, 1470–1479.
Parker, G., Roy, K., Wilhelm, K., Mitchell, P., 2001. Assessing the
comparative effectiveness of antidepressant therapies: a pro-
spective clinical practice study. J. Clin. Psychiatry 62, 117–125.
Pass, S.E., Simpson, R.W., 2004. Discontinuation and reinstitution of
medications during the perioperative period. Am. J. Health Syst.
Pharm. 61, 899–914.
Pearlman, C., 1987. High dose tranylcypromine in refractory
depression. J. Clin. Psychiatry 48, 424–425.
Price, R.B., Nock, M.K., Charney, D.S., Mathew, S.J., 2009. Effects
of intravenous ketamine on explicit and implicit measures of
suicidality in treatment-resistant depression. Biol. Psychiatry
66, 522–526.
Rabkin, J., Quitkin, F., Harrison, W., Tricamo, E., McGrath, P., 1984.
Adverse reactions to monoamine oxidase inhibitors. Part I. A
comparative study. J. Clin. Psychopharmacol. 4, 270–278.
Rabkin, J., Quitkin, F., McGrath, P., Harrison, W., Tricamo, E., 1985.
Adverse reactions to monoamine oxidase inhibitors. Part II.
Treatment correlates and clinical management. J. Clin. Psycho-
pharmacol. 5, 2–9.
Razani, J., White, K.L., White, J., Simpson, G., Sloane, R.B., Rebal,
R., Palmer, R., 1983. The safety and efficacy of combined
amitriptyline and tranylcypromine antidepressant treatment. A
controlled trial. Arch. Gen. Psychiatry 40, 657–661.
Reynolds, G.P., Riederer, P., Sandler, M., 1981. Tranylcypromine
isomers and Parkinson's disease: new aspects of an old drug. J.
R. Soc. Med. 74, 649–652.
Ribeiro, R.B., Rosa, M.A., Rigonatti, S.P., 2008. Electroconvulsive
therapy and monoamine oxidase inhibitors. Rev. Bras. Psiquiat.
30, 406–407.
Richmond, P.W., Roberts, A.H., 1964. A comparative trial of
imipramine, amitriptyline, isocarboxazid and tranylcypromine
in out-patient depressive illness. Br. J. Psychiatry 110, 846–850.
R. Ricken et al.
Ries, R.K., Wittkowsky, A.K., 1986. Synergistic action of alprazolam
with tranylcypromine in drug-resistant atypical depression with
panic attacks. Biol. Psychiatry 21, 522–526.
Robinson, D.S., 1983. High-dose monoamine oxidase inhibitor
therapy. J. Am. Med. Assoc. 250, 2212.
Robinson, D.S., Kurtz, N.M., 1987. Monoamine oxidase inhibiting
drugs: pharmacologic and therapeutic issues. In: Meltzer, H.Y.
(Ed.), Psychopharmacology: The Third Generation of Progress.
Raven press, New York, pp. 1297–1304.
Robinson, D.S., Nies, A., Davis, J.N., Bunney, W.E., Davis, J.M.,
Colburn, R.W., Bourne, H.R., Shaw, D.M., Coppen, A.J., 1972.
Ageing, monoamines, and monoamine-oxidase levels. Lancet
299, 290–291.
Roesch-Ely, D., Speck, L., Ulrich, S., Weisbrod, M., 2011. Adjuvant
tranylcypromine with second generation antipsychotic drugs in
the treatment of schizophrenia with negative symptoms: retro-
spective analysis of treatment routine of 53 patients and short
review of the literature. Psychopharmakotherapy 18, 66–74.
Sargant, W., 1975. Interactions with monoamine oxidase inhibitors.
BMJ 4, 101.
Schiele, B.C., Vestre, N.D., MacNaughton, D.V., 1963. Treatment of
hospitalised schizophrenics with trifluoperazine plus tranylcypro-
mine: a double-blind controlled study. Compr. Psychiatry 4, 68–79.
Schlessinger, A., Geier, E., Fan, H., Irwin, J.J., Shoichet, B.K.,
Giacomini, K.M., Sali, A., 2011. Structure-based discovery of
prescription drugs that interact with the norepinephrine trans-
porter, NET. Proc. Natl. Acad. Sci. USA 108, 15810–15815.
Schmauss, M., 1996. High dose tranylcypromine treatment in
treatment resistant depression. Nervenarzt 67, 390–393.
Schmauss, M., Kapfhammer, H.P., Meyr, P., Hoff, P., 1988. Combined
MAO inhibitor and tri- (tetra)cyclic antidepressant treatment in
therapyresistant depression. Prog Neuropsychopharmacol. Biol. Psy-
chiatry 12, 523–532.
Schmidt, L.G., Grohmann, R., Rüther, E., 1994. Unerwünschte
Wirkungen von Antidepressiva in der Routinebehandlung. Psy-
chopharmakotherapy 1, 6–15.
Schwartz, T.L., 2013. A neuroscientific update on monoamine
oxidase and its inhibitors. CNS Spectr. 18 (S1), 22–33.
Shulman, K.I., Fischer, H.D., Herrmann, N., Huo, C.Y., Anderson, G.
M., Rochon, P.A., 2009. Current prescription patterns and safety
profile of irreversible monoamine oxidase inhibitors: a
population-based cohort study of older adults. J. Clin. Psychia-
try 70, 1681–1686.
Singh, H., Free, R.M., 1960. A preliminary report on the use of
stelazine and parnate in chronic regressed and withdrawn
patients. Am. J. Psychiatry 117, 364–365.
Spear, F.G., Hall, P., Stirland, J.D., 1964. A comparison of sub-
jective response to imipramine and tranylcypromine. Br. J
Psychiatry 110, 53–55.
Spijker, J., Nolen, W.A., 2010. An algorithm for the pharmacological
treatment of depression. Acta Psychiatr. Scand. 121, 180–189.
Sprung, J., Distel, D., Grass, J., Bloomfield, E.L., Lavery, I.C.,
1996. Cardiovascular collapse during anesthesia in a patient with
preoperatively discontinued chronic MAO inhibitor therapy. J.
Clin. Anesth. 8, 662–665.
Stack, C.G., Rogers, P., Linter, S.P.K., 1988. Monoamine oxidase
inhibitors and anaesthesia. A review. Br. J. Anaesth. 60, 222–227.
Stewart, J.W., Deliyannides, D.A., McGrath, P.J., 2014. How treatable is
refractory depression? J. Affect. Disord. 167, 148–152.
Tariot, P.N., Sunderland, T., Cohen, R.M., Newhouse, P.A., Mueller, E.
A., Murphy, D.L., 1988. Tranylcypromine compared with L-deprenyl
in Alzheimer's disease. J. Clin. Psychopharmacol. 8, 23–27.
Taylor, B.P., Quitkin, F.M., McGrath, P.J., Stewart, J.W., 2005. Do
antihypertensives make tranylcypromine safer? Three case
reports. J. Clin. Psychiatry 66, 657–658.
Thase, M.E., 2012. The role of monoamine oxidase inhibitors in
depression treatment guidelines. J. Clin. Psychiatry 73 (S1),
10–16.
Depression in the perspective of a MAO inhibitor
Thase, M.E., Frank, E., Mallinger, A.G., Hamer, T., Kupfer, D.J.,
1992b. Treatment of imipramine-resistant recurrent depression,
III: efficacy of monoamine oxidase inhibitors. J. Clin. Psychiatry
53, 5–11.
Thase, M.E., Mallinger, A.G., McKnight, D., Himmelhoch, J.M.,
1992a. Treatment of imipramine-resistant recurrent depression,
IV: a double-blind crossover study of tranylcypromine for anergic
bipolar depression. Am. J. Psychiatry 149, 195–198.
Thase, M.E., Trivedi, M.H., Rush, A.J., 1995. MAOIs in the con-
temporary treatment of depression. Neuropsychopharmacology
12, 185–219.
Trivedi, M.H., Fava, M., Marangell, L.B., Osser, D.N., Shelton, R.C.,
2006. Use of treatment algorithms for depression. J. Clin.
Psychiatry 67, 1458–1465.
Truman, C.J., Goldberg, J.F., Ghaemi, S.N., Baldassano, C.F.,
Wisniewski, S.R., Dennehy, E.B., Thase, M.E., Sachs, G.S.,
2007. Self-reported history of manic/hypomanic switch asso-
ciated with antidepressant use: data from the Systematic
Treatment Enhancement Program for Bipolar Disorder (STEP-
BD). J. Clin. Psychiatry 68, 1472–1479.
Tyrer, P., Shawcross, C., 1988. Monoamine oxidase inhibitors in
anxiety disorders. J. Psychiatr. Res. 22 (S1), 87–98.
Van Haelst, I.M., van Klei, W.A., Doodeman, H.J., Kalkman, C.J.,
Egberts, T.C., 2012. Antidepressive treatment with monoamine
oxidase inhibitors and the occurrence of intraoperative hemo-
dynamic events: a retrospective observational cohort study. J.
Clin. Psychiatry 73, 1103–1109.
Vazquez, G.H., Tondo, L., Undurraga, J., Baldessarini, R.J., 2013.
Overview of antidepressant treatment of bipolar depression. Int.
J. Neuropsychopharmacol. 16, 1673–1685.
731
Versiani, M., Mundim, F.D., Nardi, A.E., Liebowitz, M.R., 1988.
Tranylcypromine in social phobia. J. Clin. Psychopharmacol. 8,
279–283.
Vink, J., Nolen, W.A., Verbraak, M., 1994. Is moclobemide an
alternative to tranylcypromine in treatment resistant depres-
sion? Tijdsch Psychiatr. 36, 639–646.
Vogt, A.H., 1961. The use of stelazine and parnate in chronic
withdrawn patients. Am. J. Psychiatry 118, 256–257.
Volz, H.P., Faltus, F., Magyar, I., Möller, H.J., 1994a. Brofaromine in
treatment-resistant depressed patients – a comparative trial
versus tranylcypromine. J. Affect. Disord. 30, 209–217.
Volz, H.P., Heimann, H., Bellaire, J., Laux, G., Möller, H.J., 1994b.
Brofaromine in non-endogenous major depressed inpatients –
results of a preliminary dose-finding trial versus tranylcypro-
mine. Pharmacopsychiatry 27, 152–158.
Voican, C.S., Corruble, E., Naveau, S., Perlemuter, G., 2014.
Antidepressant-induced liver injury: a review for clinicians.
Am. J Psychiatry 171, 404–415.
White, K., O'Leary, J., Razani, J., Rebal, R., Palmer, R., 1983.
Electrocardiographic effects of tranylcypromine vs. amitripty-
line. J. Clin. Psychiatry 44, 91–93.
White, K., Pistole, T., Boyd, J.L., 1980a. Combined monoamine
oxidase inhibitor-tricyclic antidepressant treatment: a pilot
study. Am. J. Psychiatry 137, 1422–1425.
White, K., Razani, J., Cadow, B., Gelfand, R., Palmer, R., Simpson,
G., Sloane, R.B., 1984. Tranylcypromine vs nortriptyline vs
placebo in depressed outpatients: a controlled trial. Psycho-
pharmacology (Berl.) 82, 258–262.
White, K., Shih, J., Fong, T., Young, H., Gelfand, R., Boyd, J.,
Simpson, G., Sloane, R.B., 1980b. Elevated platelet monoamine
oxidase activity in patients with nonendogenous depression. Am.
J. Psychiatry 137, 1258–1259.