CORRECTED FEBRUARY 13, 2008; SEE LAST PAGE

Experimental and Clinical Psychopharmacology Copyright 2007 by the American Psychological Association
2007, Vol. 15, No. 6, 529 –538 1064-1297/07/$12.00 DOI: 10.1037/1064-1297.15.6.529

Testosterone Supplementation for Depressed Men: Current Research

and Suggested Treatment Guidelines
Gen Kanayama Revital Amiaz
McLean Hospital and Harvard Medical School Chaim Sheba Medical Center

Stuart Seidman Harrison G. Pope, Jr.

Columbia University College of Physicians and Surgeons McLean Hospital and Harvard Medical School

Several lines of accumulating evidence suggest that testosterone might be effective for the
treatment of depression, especially in older men who exhibit low testosterone levels. How-
ever, despite the potential promise of this approach, the available literature of controlled
studies of testosterone in depression remains extremely limited. Therefore, testosterone
treatment of depression must still be considered an experimental procedure. At the present
state of research, it appears that testosterone might most likely show benefit as an augmen-
tation strategy in men who exhibit low or borderline testosterone levels and who show only
a partial response to conventional antidepressants. In this article, we provide some suggested
practical guidelines for the treatment of such individuals. However, it should be recognized
that these suggestions are tentative and will likely require revision as additional data become
available.

Keywords: testosterone, androgens, male, major depressive disorder, augmentation treat-

ments

In the 1880s the eminent French physician Charles-
Edouard Brown-Séquard injected himself with an extract
that he had prepared from guinea pig and dog testicles; he
reported that it gave him increased energy and vitality
(Brown-Séquard, 1889). It appears, in retrospect, that
Brown-Séquard’s preparation actually contained no active
hormones at all, but investigators have continued to pursue
his ideal. By 1935, German chemists had discovered the
primary male hormone, testosterone (David, Dingemanse,
Freud, & Laquer, 1935; Wettstein, 1935) and subsequently
began to create synthetic analogs of testosterone—the fam-
ily of hormones now known as anabolic–androgenic ste-
roids (AASs). Soon after, clinicians around the world began
to report beneficial effects from testosterone, in doses rang-
ing from 10 mg per week to as much as 700 mg per week,
in the treatment of depression (or “involutional melancho-
lia”) in aging men (Barahal, 1938; Danziger, Schroeder, &
Unger, 1944; Davidoff & Goodstone, 1942; Guirdham,
1940; Zeifert, 1942). For example, a 1948 report of 31
patients at McLean Hospital (28 men, 3 women) suggested
that testosterone might exhibit efficacy comparable to elec-
troconvulsive therapy in at least some cases (Altschule &
Gen Kanayama and Harrison G. Pope, Jr., Biological Psychiatry
Laboratory, McLean Hospital, Belmont, MA, and the Department
of Psychiatry, Harvard Medical School; Revital Amiaz, Chaim
Sheba Medical Center, Tel Hashomer, Israel; Stuart Seidman,
Columbia University College of Physicians and Surgeons.
Correspondence concerning this article should be addressed to
Harrison G. Pope, Jr., McLean Hospital, Belmont, MA 02478.
E-mail: hpope@mclean.harvard.edu
Tillotson, 1948). However, by the 1950s, the development
of tricyclic antidepressants and monoamine oxidase inhibi-
tors, together with the more widespread use of electrocon-
vulsive therapy, caused testosterone and other AASs to fall
into disuse as potential antidepressant agents. Although
occasional studies continued to appear in the 1970s and
1980s, suggesting that AASs might be useful for depression
(Itil, Hermann, Blasucci, & Freedman, 1978; Itil, Michael,
Shapiro, & Itil, 1984; Vogel, Klaiber, & Braverman, 1978,
1985), the steady appearance of new antidepressants, such
as the selective serotonin reuptake inhibitors (SSRIs), con-
tinued to capture the interest of clinicians.
In the last 10 years, however, a number of factors have
led to a renaissance of interest in testosterone and its rela-
tives as potential antidepressant agents. First, in several
large clinical trials, an improvement in mood has been
observed in hypogonadal men who received testosterone
replacement (Cunningham, Cordero, & Thornby, 1989; Mc-
Nicholas, Dean, Mulder, Carnegie, & Jones, 2003; Ver-
meulen, 2003; Wang et al., 1996, 2000), although not all
studies concurred in this finding (Haren, Wittert, Chapman,
Coates, & Morley, 2005; Sih et al., 1997; Steidle et al.,
2003). It is also well established that among normal men,
testosterone levels decline progressively with age (Ver-
meulen, 2003), and a substantial percentage of men over
age 50 may become frankly hypogonadal (Delhez, Han-
senne, & Legros, 2003). Debate persists, however, about
whether this age-dependent decline in androgen levels leads
to specific medical or psychiatric problems (McKinlay,
Longcope, & Gray, 1989; Morales, Heaton, & Carson,
2000; Seidman, 2003). Some investigators suggest that age-
associated testosterone deficiency, or “andropause,” is re-

529
530 KANAYAMA, AMIAZ, SEIDMAN, AND POPE
sponsible for many concomitants of male aging, such as
erectile dysfunction, decreased lean body mass, and osteo-
porosis, as well as for neuropsychiatric problems, such as
fatigue, loss of libido, dysphoria, and irritability (Morales,
Heaton, & Carson, 2000). Yet it has been difficult to cor-
relate hormone levels with these age-related phenomena
(McKinlay, Longcope, & Gray, 1989; Morales, Heaton, &
Carson, 2000; Seidman, 2004), and further, testosterone
replacement in elderly men is not especially effective in
reversing these symptoms (Snyder et al., 1999a, 1999b).
Moreover, there are no systematically collected data regard-
ing the effects of testosterone replacement on psychiatric
symptoms in elderly men with mildly decreased, “andro-
pausal” testosterone levels.
Nevertheless, some studies suggest that low testosterone
levels may be associated with depressive symptoms among
aging men (Barrett-Connor, von Mühlen, & Kritz-Silver-
stein, 1999; Delhez, Hansenne, & Legros, 2003; Schweiger
et al., 1999). For example, one recent study (McIntyre et al.,
2006) found significantly elevated rates of hypogonadism in
men ages 40 – 65 with major depressive disorder as com-
pared to nondepressed men; another (Shores et al., 2004)
found that initially nondepressed hypogonadal men ages 45
or older were significantly more likely than eugonadal men
to develop depression during 2 years of observation. How-
ever, not all studies have shown an association between
testosterone levels and depression, and the relationship is
likely influenced by additional factors (Booth, Johnson, &
Granger, 1999; Gray et al., 2005; Levitt & Joffe, 1988;
Seidman et al., 2002; T’Sjoen et al., 2005). Nevertheless,
the overall corpus of recent findings is certainly sufficient to
invite the speculation that testosterone replacement might
alleviate depression in some aging men with low testoster-
one levels.
A second line of recent evidence comes from observa-
tions of illicit users of AASs (Pope & Brower, 2005). These
individuals, seeking to gain muscle mass for body appear-
ance or athletic purposes, frequently use doses of testoster-
one and related AASs equivalent to 10 or 20 times the
normal daily production of testosterone in the testis. In
naturalistic studies of such AAS users, observers have re-
ported that some exhibit manic or hypomanic symptoms
during AAS exposure and/or depressive symptoms during
the hypogonadal state often precipitated by AAS with-
drawal (Choi, Parrott, & Cowan, 1990; Malone, Dimeff,
Lombardo, & Sample, 1995; Parrot, Choi, & Davies, 1994;
Pope & Katz, 1994, 2003). Although psychosocial factors
likely contribute to these effects (Riem & Hursey, 1995;
Rubinow & Schmidt, 1996), comparable mood changes
have also been documented in several laboratory studies
where supraphysiologic doses of AASs were administered
to normal volunteers under blinded conditions, suggesting
that these effects have a biological basis (Pope & Katz,
2003). Notably, these effects appear to be idiosyncratic, in
that most men who receive supraphysiologic doses of AASs
exhibit few mood changes, whereas occasional participants
exhibit hypomanic or frankly manic symptoms (Pope,
Kouri, & Hudson, 2000; Su et al., 1993). The reasons for
this variability remain speculative (Daly et al., 2001). How-
ever, these observations again support the speculation that
testosterone might have antidepressant properties, albeit
perhaps to markedly varying degrees in different individu-
als.
A third recent line of evidence arises from experience
with the administration of testosterone to men with HIV
infection. Hypogonadism is common in HIV infection
(Croxson et al., 1989), and testosterone has been widely
prescribed to HIV-positive men (Rabkin, Rabkin, & Wag-
ner, 1995). The hormone clearly exhibits physiological ben-
efits in these men, especially in counteracting the wasting
syndrome associated with HIV, but it also appears to pro-
duce mood-elevating effects over and above its physiolog-
ical effects. These effects have been documented in ran-
domized controlled trials (Grinspoon et al., 2000; Rabkin,
Wagner, & Rabkin, 2000). However, a more recent con-
trolled study failed to show a significant antidepressant
effect for either testosterone or fluoxetine in men with HIV
infection and major depressive disorder as diagnosed by
DSM-IV criteria (American Psychiatric Association, 1994),
perhaps because of the very high response observed in the
placebo arm of this study (Rabkin, Wagner, McElhiney,
Rabkin, & Lin, 2004).
A fourth development in the last 2 decades has been the
appearance of alternative routes for testosterone administra-
tion. Unlike female sex steroids such as estrogen and pro-
gesterone, testosterone is ineffective when administered
orally, because it is destroyed in first-pass metabolism (Cun-
ningham, Cordero, & Thornby, 1989). Therefore, until the
1990s, it was generally necessary to administer the hormone
by injection, making it cumbersome and difficult to use as a
routine treatment in depression. Fortunately, testosterone
has now become available in skin patches, gels, and buccal
systems; Table 1 lists formulations currently available in the
United States, together with guidelines for their administra-
tion. These new “user-friendly” formulations have likely
contributed to renewed interest in testosterone as a possible
antidepressant treatment.
Despite these promising developments, however, the po-
tential value of testosterone treatment for depression is still
unclear, and the evidence remains limited. Below, we first
review the recent literature on the use of testosterone for the
treatment of depression and then offer some suggested
preliminary clinical guidelines for use of testosterone in the
treatment of depressed men, based on our clinical experi-
ence.
Recent Studies
Only a few recent studies have assessed the effects of
testosterone in men specifically diagnosed with depression.
In a placebo-controlled trial, Seidman, Spatz, Rizzo, and
Roose (2001) administered testosterone enanthate to 30 men
with major depressive disorder and with testosterone lev-
els ⱕ 350 ng/dl. Although 38% of participants receiving
testosterone met the investigators’ criteria for treatment
response, so did 41% of the men receiving placebo, sug-
gesting that testosterone might be no more effective than
placebo for major depressive disorder. The testosterone
 SPECIAL SECTION: TESTOSTERONE TREATMENT IN DEPRESSED MEN 531

Table 1
Nonparenteral Testosterone Formulations Currently Marketed in the United States
Name Manufacturer Description Formulas Recommended dose
Androderm Watson Pharma Dermal system Patches containing either 12.2 Delivered dose
delivering 2.5 or 5 mg or 24.3 mg of T of 2.5 to 7.5 mg/
of T per day day
AndroGel Solvay Pharmaceuticals Topical gel containing 2.5- and 5-g gel packets 5 to 10 g applied to
1% T (⫽ 25 mg or 50 mg of T) skin daily
Striant Mucoadhesive Columbia Laboratories Mucoadhesive system Tablet-like system One buccal system
applied to buccal containing 30 mg of T twice daily (60
mucosa mg total)
Testim 1% Gel Auxilium Pharmaceuticals Topical gel containing 5-g tubes of gel containing 50 5 to 10 g applied to
1% T mg of T skin daily
Note. T ⫽ testosterone.

group failed to show differences from the placebo group
even on measures of sexual functioning (Seidman & Roose,
2006).
Perry et al. (2002) randomized 15 elderly eugonadal
depressed men (Hamilton Rating Scale for Depression
[HAM-D] scores ⬎ 18) to testosterone cypionate 100 mg/
week (N ⫽ 8) or 200 mg/week (N ⫽ 7). Of 5 patients with
early-onset depression (ⱕ 45 years of age), none met the
investigators’ criteria for response to testosterone,
whereas 6 of the 10 late-onset patients responded, and 5 of
these were characterized as remitted. There were no signif-
icant differences between the two dosage groups in antide-
pressant response in this small study.
Several additional studies have examined testosterone or
other AASs as possible augmentation strategies in men
already receiving antidepressant medication. In one early
study, Wilson, Prange, and Lara (1974) reported that 4 of 5
men receiving imipramine for treatment of depression de-
veloped paranoid delusions when methyltestosterone was
added to their regimen. However, in more than 3 decades
since this alarming report, no comparable cases of psychotic
effects from AAS augmentation have been described, to our
knowledge. Nevertheless, this report may have deterred
other investigators from attempting AAS augmentation of
antidepressants in the years after 1974. The next report did
not appear until almost a quarter of a century later, when
Seidman and Rabkin (1998) described 5 treatment-refrac-
tory depressed men with low or borderline plasma total
testosterone levels (200 –350 ng/dl; reference range 300 –
990 ng/dl) who were administered open-label intramuscular
testosterone enanthate, 400 mg biweekly for 8 weeks, added
to their existing antidepressant medications. The men’s
mean (SD) scores on the HAM-D declined significantly,
from 19.2 (4.4) to 4.0 (2.3) at 8 weeks.
Pope and Katz (2003) conducted an 8-week randomized
controlled trial with testosterone 1% gel, 5–10 g/day, in 22
men with low or borderline morning total testosterone levels
(ⱕ 350 ng/dl), all of whom had shown a poor or incomplete
response to antidepressants. All patients remained on their
existing antidepressant regimens throughout the study. Pa-
tients randomized to testosterone improved significantly
more than subjects on placebo on the HAM-D ( p ⬍ .001)
and Clinical Global Impression-Severity Scale ( p ⫽ .035),
but not on the Beck Depression Inventory ( p ⫽ .15). No-
tably, the authors reported significant improvement with
testosterone on both the vegetative and affective subscales
of the HAM-D, suggesting that the changes observed were
not purely attributable to physiologic effects of testosterone
such as decreased fatigue or improved libido.
Seidman et al. (2005) randomized 26 treatment-resistant
men, currently taking SSRI antidepressants, to either testos-
terone enanthate injections or to placebo for 6 weeks. The
testosterone dose was 200 mg at Weeks 0 and 1 and 400 mg
at Week 2. At Week 4, responders (individuals exhibiting ⱖ
50% reduction in HAM-D scores) again received a 400-mg
injection, whereas nonresponders received 600 mg. Unlike
the men in the Pope and Katz (2003) study, the participants
were not selected for hypogonadism; their mean total tes-
tosterone level was 418 (197) ng/dl. HAM-D scores de-
creased significantly in both the testosterone (8.4) and pla-
cebo (7.4) groups, but the groups did not differ significantly
from each other. The investigators rated 7 (54%) of the 13
testosterone recipients as responders, versus 3 (23%) of
the 13 placebo recipients ( p ⫽ .23).
Orengo, Fullerton, and Kunik (2005) administered 1%
testosterone gel, 5 g per day, or placebo in a crossover
design to 18 hypogonadal men (baseline testosterone
level ⱕ 350 ng/dl) with major depressive disorder. Six of
these participants dropped out of the study for reasons
apparently unrelated to psychiatric status, leaving 12 com-
pleters. As in the two studies above, all men remained on
their existing antidepressant regimens. Participants were
evaluated at 6 and 12 weeks of the first treatment condition,
and at 18 and 24 weeks during the crossover condition.
Depressive symptoms improved significantly from baseline
to Week 12 of testosterone treatment, but the authors did not
find a statistically significant difference between testoster-
one and placebo.
Upon comparing the above three controlled studies em-
ploying testosterone as an augmentation strategy, it is in-
teresting to note that all reported a comparable degree of
improvement in participants receiving blinded testosterone;
among study completers, the mean decline in HAM-D
scores with testosterone was 6.5 points in the Orengo et al.
(2005) study, 8.4 in the Seidman et al. (2005) study, and 8.8
in the Pope and Katz (2003) study. The principal difference
532 KANAYAMA, AMIAZ, SEIDMAN, AND POPE
among the studies appears to be in the placebo response,
which was low in the Pope and Katz study, intermediate in
the Seidman et al. study, and apparently greatest in the
Orengo et al. study. Two other factors might possibly ac-
count for differences among the study findings. First, the
Seidman et al. study, unlike the two others, was not re-
stricted to hypogonadal or borderline hypogonadal partici-
pants and thus might possibly have produced a lower suc-
cess rate than would have been achieved with exclusively
hypogonadal participants. Seven (27%) of the 26 patients in
the Seidman et al. study were hypogonadal (defined as
testosterone level ⱕ 250 ng/dl); of these, 3 of the 5 ran-
domized to testosterone met the authors’ criteria for re-
sponse, as compared to none of the 2 randomized to pla-
cebo. Second, the Orengo et al. study was limited to 5 g of
1% testosterone gel per day, which may have been inade-
quate for some subjects. In fact, the testosterone levels
achieved by subjects receiving the 1% gel in this study
ranged as low as 210 ng/dl, suggesting that some subjects
remained frankly hypogonadal despite testosterone admin-
istration. The Pope and Katz study also reported difficulty
achieving adequate testosterone levels in some subjects,
despite a protocol that allowed use of up to 10 g of gel per
day. In the Seidman et al. study, however, use of robust
doses of injectable testosterone presumably ensured ample
plasma levels in all subjects.
None of the three recent augmentation studies reported
clinically significant adverse effects, with the exception of 1
subject in the Pope and Katz (2003) study who reported
increased difficulty initiating urination while receiving tes-
tosterone, suggesting a possible exacerbation of benign
prostatic hypertrophy. Notably, none of the subjects in any
of the studies displayed psychotic symptoms in the manner
of the patients reported 30 years earlier by Wilson, Prange,
and Lara (1974; see above), either during blinded adminis-
tration of testosterone or in subsequent open-label treatment
with the hormone. However, it should be noted that none of
the subjects in any of the studies was receiving a tricyclic
antidepressant.
In summary, despite the seeming promise of testosterone
as an antidepressant, supporting systematic data remain
limited. Small sample sizes and differences in methodology
further limit interpretation of the findings. Similar conclu-
sions have emerged from another recent review examining
many of these same studies (Shamlian & Cole, 2006).
Pending larger and more sophisticated trials, it seems rea-
sonable to speculate that if testosterone is effective, the best
candidates for treatment may be men who are demonstrably
hypogonadal, currently taking an existing antidepressant
with inadequate response, and capable of attaining adequate
plasma levels from the testosterone preparation being ad-
ministered to them.
Clinical Suggestions
As illustrated by the above discussion, treatment of de-
pression with testosterone should still be considered an
experimental procedure. However, for clinicians who wish
to attempt a trial of testosterone in depressed male patients,
we offer suggestions based on our experience. The follow-
ing discussion and the accompanying flowchart (see Figure
1) applies exclusively to treatment of depressed men; al-
though testosterone in small doses may well offer beneficial
effects for depression or low libido in women (Shifren et al.,
2000), research in women remains extremely limited.
Clearly, use of large doses of testosterone in women is
inappropriate, due to the drug’s masculinizing effects.
Moreover, in a recent Endocrine Society consensus report
(Wierman et al., 2006) a panel of leading experts recom-
mended against diagnosing and/or treating androgen defi-
ciency in women.
In men with major depressive episodes who appear to be
candidates for biological treatment, data do not support the
use of testosterone as a first-line antidepressant treatment, as
a wide range of standard antidepressant medications of
well-established safety and efficacy are available. As noted
above, in the setting of comorbid major depression and
hypogonadism, there is only one small placebo-controlled
study assessing testosterone replacement alone as an anti-
depressant, and this study was negative. Given the inade-
quate power of that study to detect a small or highly variable
signal, there is a clear need for more research to determine
whether testosterone alone might be efficacious for depres-
sion. Currently it seems best to consider testosterone as a
potential adjunctive treatment for men who are partially
responsive to conventional antidepressants.
It should also be noted, in this context, that there are other
well-established augmentation strategies for patients with
an incomplete response to standard antidepressant regi-
mens, including thyroid and lithium (Nierenberg et al.,
2006; Sussman & Joffe, 1998). For example, triiodothyro-
nine has been shown to effectively augment the effects of
the SSRI sertraline in a recent controlled trial that excluded
patients with hypothyroidism (Cooper-Kazaz et al., in
press). Lithium augmentation is somewhat more cumber-
some than thyroid augmentation but is also well established
in controlled trials as an augmentation strategy for men only
partially responsive to antidepressants (Bschor & Bauer,
2006). Also, individuals poorly responsive to an SSRI an-
tidepressant may benefit from the addition of bupropion or
buspirone (Trivedi et al., 2006). Finally, in clinical prac-
tice—and with only limited supporting controlled data
(McGrath et al., 2006)— clinicians routinely use other antide-
pressant combinations to enhance response (Thase, 2003).
Given these choices, psychiatric clinicians will need to
decide how best to rank the various augmentation strategies
in men who exhibit a partial response to antidepressants.
Many men, having heard about testosterone replacement
therapy from nonscientific sources, may be eager to try this
treatment in the hope of achieving renewed youth and
virility, and clinicians may need to explain to such patients
that other, less glamorous strategies have a better chance of
helping their mood disorder.
The first—and absolutely essential—step in the assess-
ment of a patient for possible testosterone treatment, is to
obtain a total testosterone level. Testosterone should be
measured in the morning, preferably before 10 a.m., be-
 SPECIAL SECTION: TESTOSTERONE TREATMENT IN DEPRESSED MEN 533

Abnormal

Figure 1. Tentative guidelines for testosterone (T) augmentation of antidepressants in men.

PSA ⫽ prostate-specific antigen; HPT ⫽ hypothalamic–pituitary–testicular.

cause the hormone exhibits a diurnal pattern of secretion,
with peak levels early in the day and a gradual decline
thereafter (Winters, 1991). The normal range for total tes-
tosterone levels is generally considered to be approximately
300 –1000 ng/dl; if a patient’s morning testosterone level is
below or close to the bottom of this range, this finding may
strengthen the case for a trial of testosterone. It should be
cautioned, however, that there is no concrete evidence that
testosterone preferentially exhibits antidepressant effects in
men with low endogenous testosterone levels. Nevertheless,
it seems likely that hypogonadal or borderline hypogonadal
men with depression will be the best candidates for a trial of
exogenous testosterone replacement. In the same context,
men who report low libido and fatigue— classic hypogo-
nadal symptoms—might perhaps be more likely to achieve
antidepressant benefit from testosterone replacement,
534 KANAYAMA, AMIAZ, SEIDMAN, AND POPE
though again, there are no systematic data available regard-
ing predictors of mood-enhancing effects of testosterone.
It should also be cautioned that total testosterone levels
do not necessarily reflect biologically active testosterone, as
a substantial portion of testosterone is bound to sex hor-
mone binding globulin (SHBG) and is less biologically
active (Emadi-Konjin, Bain, & Bromberg, 2003). More
sophisticated and expensive measures, such as the free
testosterone level, or calculations of bioavailable testoster-
one based on SHBG levels, may ultimately prove more
useful in predicting which men will display an antidepres-
sant response to testosterone, but at present this issue re-
mains entirely speculative. Notably, one recent comparison
of depressed and nondepressed middle-aged men (Mc-
Intyre et al., 2006) found that total testosterone levels were
at least as good as calculated bioavailable testosterone lev-
els in distinguishing between the two groups. Thus, at the
present stage of knowledge, a total testosterone level is
sufficient as a practical screening test for clinicians consid-
ering a trial of testosterone augmentation therapy for de-
pression.
If a patient exhibits low testosterone levels, clinicians
should first consider the possibility of treatable causes of
hypogonadism. For example, it is important to elicit a
history of use of medications (especially licit or illicit use of
opiates; see for example Daniell, 2002; Daniell et al., 2006),
as well as herbal preparations or home remedies. The pos-
sibility of hypothalamic or pituitary disease should also be
considered; evidence of visual field disturbances, head-
aches, seizures, or neurological abnormalities should
prompt additional evaluation. Pituitary function may also be
assessed by determination of luteinizing hormone and fol-
licle-stimulating hormone levels. If testosterone levels are
unusually low (for example less than 150 ng/ml in a middle-
aged man), further evaluation of pituitary function by an
endocrinologist, including pituitary imaging studies, may be
warranted. For further details, see published consensus rec-
ommendations for evaluation of hypogonadal men (Amer-
ican Association of Clinical Endocrinologists, 2002).
If a trial of testosterone appears reasonable, after taking
into account the above considerations, the clinician must be
careful to ensure that there is no evidence of prostate cancer,
as determined by a normal prostate-specific antigen (PSA)
level (generally less than 4.0 ng/ml) and a normal digital
rectal examination of the prostate. It should be recognized,
however, that these measures do not exclude the possibility
of prostate cancer; in fact, one study (Morgentaler & Rho-
den, 2006) found biopsy evidence of prostate cancer in 32
(13.2%) of 242 hypogonadal men with a PSA of less
than 4.0 and a normal digital rectal examination. In this
study, cancer was much more common in hypogonadal men
with lower total testosterone levels (less than 250 ng/ml)
and/or higher PSA levels (2.0 – 4.0), suggesting that partic-
ular caution should be exercised in considering testosterone
treatment for men exhibiting these features. Breast cancer in
men is also an absolute contraindication to testosterone
treatment. And, because exogenous testosterone generally
increases the hematocrit (Tenover, 2003), it is important to
assess hematocrit prior to initiation of treatment.
Next, the clinician should consider which testosterone
preparation to use. Although 17-alkyl derivatives of testos-
terone, such as methyltestosterone, have the advantage that
they may be administered orally, they also may be hepato-
toxic and are virtually never used (Westaby, Ogle, Paradi-
nas, Randell, & Murray-Lyon, 1977). Testosterone is avail-
able in several long-acting esters (testosterone cypionate,
enanthate, decanoate, etc.) for parenteral administration, but
intragluteal injections are generally less practical and may
produce widely fluctuating testosterone levels over the dos-
ing period (Dobs et al., 1999). We generally recommend
one of the noninjectable testosterone preparations listed in
Table 1; in terms of daily cost, these formulations are more
expensive than parenteral testosterone but are far more
convenient. We suggest that the clinician discuss these
various options with the patient.
Testosterone gels, patches, and buccal systems may yield
quite different plasma levels from one patient to another;
therefore, it is important to reassess the total testosterone
level after the patient has been on treatment for several days
to a week. If the level has not risen to at least the middle of
the physiologic range (at least 500 ng/dl), we would suggest
a dosage increase to ensure that the patient is receiving a
fully adequate clinical trial. Conversely, occasional patients
will exhibit supraphysiologic levels (greater than 1000 ng/
dl) even with conventional doses of testosterone; although
side effects are uncommon even with markedly supraphysi-
ologic testosterone levels (Pope, Kouri, & Hudson, 2000), it
nevertheless seems reasonable to reduce the testosterone
dose in such patients in order to bring the level into the
physiologic range.
In our experience, patients who respond to testosterone
augmentation typically exhibit improvement within less
than 4 weeks and almost certainly within 6 weeks. There-
fore, as shown in Figure 1, the decision tree branches at the
6-week mark of treatment. If the patient has not shown a
clear improvement by this point, we suggest that the clini-
cian stop testosterone immediately, because chronic admin-
istration of exogenous testosterone suppresses the hypo-
thalamic–pituitary–testicular (HPT) axis, leading to gradu-
ally reduced endogenous testosterone production. If
testosterone is administered for only 6 weeks and then
promptly stopped, HPT-axis function has been only briefly
suppressed, and normal testicular production of testosterone
will resume quickly. On the other hand, if testosterone is
continued for a longer period, then greater degrees of HPT-
axis suppression will occur, and rebound hypogonadism
becomes increasingly problematic if testosterone is stopped
abruptly at a later point. Therefore, it is important to “cut
one’s losses” and stop testosterone promptly if the drug is
not clearly effective.
A second branch of the decision tree, and arguably the
most difficult, involves patients who display what might be
called the “Brown-Séquard effect” described at the begin-
ning of this article: If a man knows (or believes) that he is
receiving male hormones, the power of suggestion can be
very strong. In placebo-controlled studies of testosterone
augmentation, we have observed participants who reported
dramatic improvements in mood, enthusiasm, energy, and
 SPECIAL SECTION: TESTOSTERONE TREATMENT IN DEPRESSED MEN
libido— only to discover that they had been receiving a
placebo throughout the study. Thus, we strongly recom-
mend that clinicians try discontinuing testosterone at some
point after depressive remission is stable, and if relapse then
occurs, consider experimenting with “on-and-off” trials. If
such on-and-off trials convincingly indicate a bona fide drug
effect, then it is more reasonable to commit to longer-term
treatment.
The third branch of the decision tree involves patients
who display an apparently unequivocal response to testos-
terone, either with initial treatment or through the evidence
of on-and-off trials. In such cases, testosterone may be
maintained for months or even years, but patients must be
cautioned that the risks of long-term testosterone supple-
mentation are not fully understood. In particular, testoster-
one is known to play a permissive role in the development
of prostate cancer. Although present data do not suggest that
chronic testosterone administration leads to the progression
of preclinical or clinical prostate cancer (Seidman & Roose,
2000), there are as yet no very large, long-term epidemio-
logic studies of this issue, and a slight increase in long-term
cancer risk cannot be excluded. Certainly, patients receiving
long-term testosterone treatment should have regular checks
of PSA levels and periodic digital rectal examinations to
monitor prostate status. Indeed, once a clear benefit of
testosterone is established, we recommend that the patient
be referred to a urologist or endocrinologist for continuing
hormone replacement and monitoring. As prostate cancer
may be detectable even in men with normal PSA and digital
prostate examination, it is important to adhere to a rigorous
monitoring strategy for early detection of prostate events in
hypogonadal men receiving testosterone therapy, as recom-
mended by the Endocrine Society’s guideline for testoster-
one therapy of androgen-deficient men (Bhasin et al., 2006).
Although there has been some speculation that long-term
testosterone administration might increase cardiovascular
disease risk, other data suggest that treatment might actually
be associated with reduced risk (Tenover, 2003). Again,
patients must be advised that in the absence of long-term
multicenter trials, the relative risks and benefits of testos-
terone in this respect are not as yet fully known.
Another major consideration in long-term testosterone
administration is suppression of HPT-axis function, as de-
scribed above. Patients should be informed that they cannot
stop testosterone abruptly after prolonged use without risk-
ing rebound hypogonadism, which may trigger a recurrence
of their depressive symptoms. Thus, the testosterone dose
must be tapered over several weeks while mood is moni-
tored. Alternatively, human chorionic gonadotropin, admin-
istered intramuscularly every 2 days for several weeks, can
be used to restimulate testicular function more quickly, thus
minimizing hypogonadal symptoms. However, many psy-
chiatrists may feel uncomfortable prescribing this treatment
and may prefer to refer the patient to an endocrinologist in
such cases.
Most other side effects of testosterone are mild, although
some men experience truncal acne, fluid retention, breast
soreness, or frank gynecomastia. Polycythemia may occur
535
in some men receiving testosterone, so that the hematocrit
should be periodically assessed.
Given the above considerations, the decision to prescribe
long-term testosterone augmentation is more complicated
than deciding to prescribe conventional antidepressants for
prolonged periods. At the present state of knowledge, we
feel that long-term testosterone should be reserved only for
those patients who have failed more conventional treat-
ments and who exhibit an unequivocal antidepressant re-
sponse to the hormone. Even in these cases, it seems wise to
attempt to eventually discontinue testosterone in the hopes
that the underlying depressive episode may have remitted.
Conclusions
Several lines of evidence suggest that testosterone and
other AASs might be effective for the treatment of depres-
sion, especially in aging men who exhibit hypogonadism.
However, despite the promise of this therapeutic strategy,
the available literature of controlled studies remains ex-
tremely limited and testosterone treatment must still be
considered an experimental procedure. Pending more defin-
itive data, it appears that testosterone might most likely
show benefit as an antidepressant-augmentation strategy in
men who exhibit low or borderline low morning testoster-
one levels and who show only a partial response to conven-
tional antidepressants. In this article, we have offered some
suggested guidelines for the treatment of such individuals.
However, it should be recognized that these guidelines are
tentative and will likely require revision as additional data
accumulate in the field.
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Received January 8, 2007
Revision received March 12, 2007
Accepted March 12, 2007 䡲

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 Correction to Kanayama et al. (2007)

The article, “Testosterone Supplementation for Depressed Men: Current Research and Suggested
Guidelines,” by Gen Kanayama, Revital Amiaz, Stuart Seidman, and Harrison G. Pope Jr. (Exper-
imental and Clinical Psychopharmacology, 2007, Vol. 15, No. 6, pp. 529 –538) contained an error.
In the “Recent Studies” section (pp. 531–532), citations to Pope and Katz (2003) should have been
to Pope, Kanayama, Cohane, Siegel, and Hudson (2003) to reflect the following source, which was
omitted from the reference list:
Pope, H. G., Jr., Kanayama, G., Cohane, G., Siegel, A., & Hudson, J. I. (2003). Testosterone gel
supplementation for men with refractory depression: A randomized placebo-controlled trial. Amer-
ican Journal of Psychiatry, 160, 105–111.
DOI: 10.1037/1064-1297.16.2.. . .