Testosterone Supplementation for Depressed Men: Current Research and Suggested Treatment Guidelines

Abstract

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. However, 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 augmentation 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.

Full text

Testosterone Supplementation for Depressed Men: Current Research
and Suggested Treatment Guidelines
Gen Kanayama
McLean Hospital and Harvard Medical School Revital Amiaz
Chaim Sheba Medical Center
Stuart Seidman
Columbia University College of Physicians and Surgeons Harrison G. Pope, Jr.
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-Se´quard 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-Se´quard, 1889). It appears, in retrospect, that
Brown-Se´quard’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 &
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-
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
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
529
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