5. Steroids and Mental Health
Research and anecdotal information suggested some time ago that steroids have among their many side effects various mental disturbances including schizophrenic symptoms and manic depressive illnesses even though estrone was used successfully in both males and females in the treatment of depression and other mental disturbances occurring with menopause and what would now probably be referred to as andropause beginning in the mid-1930s. Glass (1950) reported that psychoneurotic patients responded more favourably to androgen-estrogen mixtures because these mixtures impart an optimum sense of well-being. 35 years later, Sherwin and Gelfand (1985) reported similar findings of increased energy level and well-being in female surgical menopause patients receiving either a combined estrogen-androgen drug or androgen alone as compared with those receiving estrogen alone or placebo. Although quantification of mood states was generally lacking, it is noteworthy that 23 of 24 studies cited by Kopera (1976) report improvements in psychic as well as physical state, appetite and weight gain in surgical and chronically ill patients treated with anabolic-androgenic steroids. Another 11 of 17 controlled and 11 of 14 uncontrolled clinical trials in geriatric patients cited by Kopera also showed positive anabolic-androgenic steroid effects on physical activity, energy and mood.
It is now well known that, in excess, glucocorticoids can produce extreme emotional instability, ranging from euphoria to suicidal despondency (Hall 1980). Studies of patients with Cushing’s disease indicate that up to 20% could be termed psychotic. Depression is the most common manifestation and suicidal attempts are reported in approximately 10% of cases. Other psychological manifestations include irritability, insomnia, difficulty concentrating, paranoid delusions, hallucinations, and less often, excitement, anxiety, apathy, disorientation, loss of recent memory, and acute organic brain syndrome. Schizophrenic symptoms may also, but rarely, occur. With drug-induced Cushing’s syndrome, in contrast, the most common psychological effect is euphoria, although acute toxic psychosis can also occur.
Mental disorders associated with corticosteroid administration have been documented since the early 1950s (Borman & Schmallenberg 1951; Brody 1952; Byyny 1976; Clark et al. 1952; Glasser 1953). Rome and Braceland (1952) commented that the occurrence of a certain small percentage of psychotic reactions as a compilation of the diseases for which various steroids are administered was to be expected. Train and Winkler (1962) reported a case of homicide involving a woman who had psychotic depression while on corticotrophin and killed her son. Reports continue with still another corticosteroid-related psychotic episode and attempted homicide in 1989 (d’Orban 1989).
Ling et al. (1981) have reviewed the literature to determine the characteristics of corticosteroid-induced mental disturbances and have concluded that: (a) while dosage may be related to the risk of developing mental disturbances, neither dosage nor duration of treatment seems to affect the time of onset, duration, severity, or type of mental disturbances; (b) euphoria as well as depression and psychotic reactions are the most common manifestations of corticosteroid-induced mental disturbances; (c ) females seem to be more prone to these disturbances than males; (d) patients with past mental illness are not necessarily predisposed to such disturbances; and (e) corticosteroid-induced mental disturbances are usually reversible upon dose reduction or discontinuation of the drug. Ling et al. (1981) concluded that there are no simple models to explain the psychotic reactions, anxiety, or agitation seen in corticosteroid-induced mental disturbances. Kaufmann et al. (1982) concluded, in their case report and brief overview, that there are apparently no characteristic symptoms of corticosteroid psychosis. Lewis and Smith (1983) reported in a subsequent review of 14 previously unreported cases of steroid-induced psychiatric syndromes, 79 cases from the medical literature and 29 studies of the clinical efficacy of steroids in various medical illnesses that severe psychiatric reactions occur in approximately 5% of steroid-treated patients, but their review [which contained additional cases not included in Ling et al. (1981)] indicated that a significant proportion of these patients already have existing affective and/or psychotic symptoms. None of their 14 cases had a past history of psychiatric illness unrelated to steroid therapy; 6 (43%) of their 14 cases were thought to have evidence of a premorbid personality disorder; of 41 cases in the literature, 17% had a prior history of psychiatric illness unrelated to steroids; and 52% of the 29 cases were reported to have had an abnormal premorbid personality. Alcena and Alexopoulos (1985) also recently concluded both from their data and a review of the literature on corticosteroid-induced psychiatric disorders that: (a) the pathogenesis of psychiatric symptoms during corticosteroid therapy is unknown; (b) development of psychiatric complications in patients receiving corticosteroids is probably dose-dependent; (c ) the type of psychiatric manifestations is variable; (d) it is unclear whether a history of psychiatric disorders increases the risk for psychiatric problems from corticosteroids; and (e) in the majority of patients, psychiatric complications remit when the dosage of corticosteroids is reduced or administration discontinued.
With respect to withdrawal symptoms, it is worth noting that symptoms of Addison’s disease include apathy, depression, fatigue, a general lack of interest, initiative and motivation, and an overall negativism (Hall 1980). In acute Addison’s disease a typical organic psychosis develops with memory deficit and clouding of consciousness. Administration of aldosterone improves electrolyte balance, but corticosteroid administration is necessary to correct the personality disturbance, EEG abnormalities and altered sensory thresholds.
Considering then the structural similarities of cortical and anabolic steroids and their multiple additive and synergistic as well as competitive actions, it is not surprising that their administration would result in some similar effects on mood and behaviour. Furthermore, anabolic-androgenic steroid administration has been reported to alter glucocorticoid metabolism (James et al. 1962), and high doses of anabolic-androgenic steroids given to athletes have been shown to dramatically elevate serum and urinary cortisol levels (Hervey et al. 1976), although other studies have not corroborated this latter finding (Alen et al. 1985).
Androgens, on the other hand, have been used in the treatment of mental disorders for over 50 years. Werner et al. (1934) used theelin (estrone) to treat female patients suffering from involutional melancholia (depression) and reported improvement in 18 of the 20 cases attended. 90% (versus 16% in a control treatment) of the 39 female patients (34 to 58 years) with involutional melancholia treated with daily intramuscular injections of theelin over 6 months showed slight to marked improvement in a study by Werner et al. (1936). Using larger doses, Ault et al. (1937) later treated 14 female cases of involutional melancholia with a recovery rate of 92%. However, although no adverse reactions were reported, the results for treatment of mental disorders with theelin was not always successful (Schube et al. 1937).
In a review of the literature, Danziger (1942) reported that while estrone therapy was not highly successful for the treatment of female involutional melancholia, the incidence of recovery or marked improvement was better than no treatment and, in his own investigation, found 4 of 7 female patients benefited from the daily oral administration over several month of diethylstilbestrol.
Schmitz (1937) produced improvement with testosterone propionate in 86% of 42 cases with symptoms such as depression and impotence in males in the involutional age. Foss (1937) relieved depression in a eunuch by the daily injection of 20mg of testosterone propionate.
Hamilton (1937) reported that a 27-year-old male hypogonadal subject treated with testosterone acetate (a total of 550mg over a period of 1 month) became more energetic, virile and self-assured during therapy. Testosterone propionate 10mg 3 times weekly relieved the subjective symptoms (anxiety, depression, fatigue) in 2 male climacteric patients (Werner 1939). Two cases diagnosed as male climacteric (involutional melancholia) and treated with moderate amounts of testosterone propionate (10 to 30 mg/week) for short periods of time (6 to 8 weeks) by Thomas and Hill (1940) made ‘remarkable improvement’ both during and subsequent to treatment. Likewise, Guirdham (1940) reported mental improvement in 4 males suffering from a variety of psychological disorders after being treated with intramuscular injections of testosterone propionate and androsterone benzoate (5 mg/day).
Lamar (1940) also reported improvement in 4 male climacteric patients treated with varying doses of testosterone propionate over several months. Palmer et al. (1941) reported improved mental states in 5 of 10 male involutional melancholia patients treated with testosterone propionate over several months. 65% of the 20 male patients (versus 46% in the control group receiving routine hospital procedures) suffering from involutional psychoses treated with intramuscular injections of testosterone propionate (30 to 75 mg/week) for a period of 6 to 12 weeks responded well in a study by Davidoff and Goodstone (1942).
Using ‘massive dose’ (1300mg over 40 days) testosterone propionate therapy to treat 5 cases of male involutional psychosis, Zeifert (1942) reported 2 patients improved sufficiently to warrant release, 2 others improved during treatment but relapsed shortly thereafter, and 1 failed to show any change. No harmful effects were observed during the experiment despite the administration of relatively high doses of testosterone propionate.
Werner (1943) reported that 24 of 26 middle-age male climacteric patients receiving intramuscular injections of testosterone propionate 30 to 75 mg/week benefited by relief of symptoms and a sense of well-being. Heller and Myers (1944) recommended regular intramuscular injections of testosterone propionate 25 mg to obtain satisfactory therapeutic results in the male climacteric.
Danziger and Blank (1942) reported an overall success rate of nearly 70% for androgen treatment of depressed males in a review of the literature and, in their own investigation, found that 3 of 5 patients benefited from the weekly intramuscular administration of 75 to 150 mg of testosterone propionate. Two years later, Danziger et al. (1944), in another literature review, reported that the incidence of prompt recovery for testosterone-treated male patients with involutional melancholia was significantly higher than the incidence of prompt spontaneous recovery for control patients. In the same investigation, using 9 additional male patients with involutional melancholia, the authors found recovery and improvement in 6 patients following injections of testosterone propionate (25mg) 3 times per week over several month.
Altschule and Tillotson (1948) found that intramuscular administration of testosterone in large doses (350 mg/week) over 2 to 3 weeks was followed by remission of mental symptoms in 18 of the 31 (28 male) psychiatric patients that they treated.
Again, as with estrone, results with testosterone propionate were not always so positive. In 1939, the Council of Pharmacy and Chemistry of the American Medical Association refused to accept testosterone for New and Nonofficial Remedies stating, ‘the involutional melancholia of males, for which testosterone has been suggested, has not been subjected to adequate trials, to justify androgenic therapy other than on an experimental basis.’ No ‘noticeable improvement’ in mental condition was found in 5 cases of male involutional melancholia who were treated with intramuscular injections of testosterone propionate 10mg 3 times weekly for a period of 3 to 4 weeks by Barahal (1938). Barahal (1940) also found little or no change in the mental condition of 7 psychotic male homosexual patients who were treated with intramuscular injection of testosterone propionate (25mg) 3 times weekly for 18 months. In addition, Pardoll and Belinson (1941) reported that mental improvement was not sufficiently pronounced to warrant administering testosterone propionate as routine treatment for the male involutional psychoses after treating 11 males with 10mg doses of testosterone propionate twice weekly for 3 months and observing behaviour for 2 months following cessation of therapy.
11 of 12 male involutional melancholia patients (53 to 64 years), treated with intramuscular injections of testosterone propionate (1500mg) over 8 months, showed no improvement either during or after treatment, leading Kerman (1943) to conclude that testosterone propionate had little or no effect in the treatment of male involutional melancholia. Simonson et al. (1944) found significantly increased (compared to a placebo period) fusion frequency of flicker and back-muscle strength in 6 older male subjects (46 to 67 years), who had complained of fatigability, following oral treatment with methyl testosterone (30 to 40 mg/day) over 6 to 45 weeks. The results appear to be compatible with the hypothesis that maintenance of a higher level of male sex hormone has an influence on the depression of working capacity with age.
Strauss et al. (1952) reported improved mental states in 6 of 8 male patients with schizophrenic illness treated with various doses of dehydroisoandrosterone over several weeks. However, increased aggressiveness and nervous tension occurred in the other 2 patients during the course of treatment. Sands and Chamberlain (1952) reported significant improvement in 13 juveniles with inadequate personality following the administration of dehydroisoandrosterone (10 to 20 mg/day) for 2 to 11 weeks. Again, however, those patients who tended ‘to be overaggressive in mental make-up were made worse and appeared overstimulated by the drug.’
Burnett (1963) used a placebo-controlled study with 38 chronically ill male and female geriatric mental patients (36 of whom were past the age of 60) to determine the effect of anabolic-androgenic steroids (6 mg/day of stanozolol for 5 month) and found that ‘mental outlook’ improved in 5 of the 18 anabolic-androgenic steroid-treated patients compared with 1 of the 20 placebo-treated patients. MacMaster and Alamin (1963) treated 47 underweight, mentally disturbed female patients ranging in age from 15 to 86 years with methandrostenolone 5 to 15 mg/day over 29 to 60 days and reported an improvement in appetite, a feeling of well-being and an improved psychological attitude. Tec (1974) has described limited success in improving ‘general psychic condition’ following administration of the decanoate ester of nandrolone (2 intramuscular injections of 25mg over 2 weeks) in a young female suffering from anorexia nervosa. A sense of increased well-being was also reported by Sansoy et al. (1971) in a study of 34 male and female mental patients (ages 22 to 104 years) who received 15 to 20mg of oxandrolone daily for 8 weeks. Wynn and Landon (1961) reported that a wide range of dose (25 to 100 mg/day) and length of administration (6 to 260 days) of methandienone produced a sense of well-being and increased confidence without restlessness, nervousness, or insomnia in 19 of 30 male and female patients with various disorders. In a double-blind study by Jakobovits (1970) of 100 impotent elderly male patients, a favourable response was seen in 78% of the patients treated with methyltestosterone thyroid for 1 month, whereas a favourable response was seen in only 40% of the cases treated with placebo. No adverse effects or chemotoxicity was noted in any of the patients.
Itil (1976) treated 5 male psychiatric (depressed) patients with daily doses of 2 to 6mg of the nonaromatisable oral androgen mesterolone for 24 days and within a week subjects showed a decrease in depressive mood, sadness, and particularly feelings of inadequacy based on clinical observations. Increasing the dosage from 25 to 200 mg/day resulted in 4 of 5 other male psychiatric (depressed) patients demonstrating improved mental states. Other studies by Itil et al. (1974, 1979) have confirmed that this compound results in electroencephalographic effects that are, as previously indicated, depending upon the dose, similar to stimulants (such as amphetamines) and tricyclic antidepressants. Beumont et al. (1972) found administering methyltestosterone (25 mg/day) over 8 weeks to a male patient resulted in the specific and rapid loss of both depressive and phobic symptoms. Pope and Katz (1988) report the prompt remission of weekly panic attacks in a 40-year-old female subject with a history of panic disorder following self-administration of oxandrolone (20 mg/day). Vogel et al. (1985) compared the antidepressant effects of amitriptyline (75 mg/day, up to a maximum of 300 mg/day) and mesterolone (100 mg/day, up to a maximum of 550 mg/day orally) in a double-blind parallel treatment design with 34 depressed male outpatients and found that the 2 drugs were equally effective in reducing depressive symptoms and that mesterolone produced significantly fewer adverse effects than amitriptyline.
Wilson et al. (1974), in contrast, found that 4 of 5 depressed men treated with methyltestosterone (15 mg/day orally) and the tricyclic antidepressant imipramine (25 to 50 mg/day) orally simultaneously, promptly showed a paranoid response that cleared rapidly when treatment with the hormone was discontinued. They hypothesized that the shift from depression to a paranoid reaction may have resulted from an increase in aggression, which in turn may have been the result of the interplay between the hormone and the drug and the effects of this interplay on brain monamine metabolism. The findings of Wilson et al. (1974) are not unexpected given the fact that testosterone is known to inhibit MAO activity. Concomitant administration of a substance (such as imipramine) which would additionally elevate monoamine levels by inhibiting reuptake could well be expected to induce moodiness, paranoia, and depression, a biphasic response that has been shown to occur with administration of increasing doses of estrogen, another inhibitor of MAO.
Even after reviewing the report of Wilson et al. (1974), Hollister et al. (1975) suggested that ‘small doses of androgens might be useful as adjuncts to potentiate the effects of small doses of tricyclics in patients who cannot tolerate the anticholinergic side effects of large doses.’ Clinical studies and hormonal therapy for mental illness have, however, presumably been preempted by the development and marketing of a wide variety of newer pharmacological agents.
Tilzey et al. (1981) have also reported a case involving a 66-year-old male patient with symptoms of severe anaemia who developed toxic confusional state and choreiform movements after several months of treatment with an anabolic-androgenic steroid (oxymetholone 200 to 300 mg/day orally) and improvement upon withdrawal of the drug. This represents a relatively large dose since the normal daily dose is between 50 and 200 mg/day. The onset of symptoms and remission following cessation of administration suggested that the drug played a significant role in the aetiology of the observed symptoms.
The findings of the preceding studies nevertheless generally indicate positive rather than negative effects following androgen therapy in mental (especially depressed) patients. However, it is unknown whether long term use or use of pharmacological doses by otherwise healthy individuals, particularly adolescents, might result in similar outcomes. A summary of these studies is provided in table III.
Originally appearing in Sports Medicine 10(5) 303-337. 1990. Copyright © 1990 by Adis International Limited. All rights reserved. Reprinted by MESO-Rx with permission. Any duplication of this document by electronic or other means is strictly prohibited.