Background and Objectives: Testosterone deficiency has been implicated in the etiology of depression although there is an ongoing debate on the nature of this association. There is a paucity of data about the psychological impact of hypogonadism in genetic disorders associated with testosterone deficiency. Methods:A 57-year-old male is described who was referred for treatment resistant depression. His history showed infertility and lowered testosterone. A selective literature review is given to clarify the patient's clinical condition. Results: Cytogenetic analysis demonstrated a Robertsonian translocation between chromosomes 13 and 14 that accounted for his infertility. The psychopathological picture did not meet the criteria for a major depressive disorder but was characterized by symptoms of apathy or avolition. These symptoms were most probably aggravated by previous long lasting treatment with antidepressants. Conclusions: Testosterone deficiency may be related to motivational deficits that should not be misunderstood for depressive illness. Apathy is probably an underestimated side effect of antidepressants

Egger, J.I.M. (Jos)

Erp, F. (Femke) van

Tuerlings, J. (Joep)

Tuinier, S. (Siegfried)

Verhoeven, W.M.A. (Wim)

Background and Objectives: Testosterone deficiency has been implicated in the etiology of depression although there is an ongoing debate on the nature of this association. There is a paucity of data about the psychological impact of hypogonadism in genetic disorders associated with testosterone deficiency. Methods:A 57-year-old male is described who was referred for treatment resistant depression. His history showed infertility and lowered testosterone. A selective literature review is given to clarify the patient\'s clinical condition. Results: Cytogenetic analysis demonstrated a Robertsonian translocation between chromosomes 13 and 14 that accounted for his infertility. The psychopathological picture did not meet the criteria for a major depressive disorder but was characterized by symptoms of apathy or avolition. These symptoms were most probably aggravated by previous long lasting treatment with antidepressants. Conclusions: Testosterone deficiency may be related to motivational deficits that should not be misunderstood for depressive illness. Apathy is probably an underestimated side effect of antidepressants

Erasmus University Digital Repository

Eur. J. Psychiat. Vol. 22, N.° 4, (195-199)2008Keywords: Hypogonadism, Robertsonian translo-cation, Depressive disorder, Apathy, Avolition.Avolition in a patient with hypogonadismWillem Verhoeven*,**Siegfried Tuinier*Jos Egger*,***Femke van Erp****Joep Tuerlings** Vincent van Gogh Institute for Psychiatry,Department of Clinical Research, Venray** Erasmus University Medical Centre,Department of Psychiatry, Rotterdam*** Behavioural ScienceInstitute/Department of Psychology,Radboud University, Nijmegen**** Department of Human Genetics,Radboud University Nijmegen, MedicalCentre, NijmegenTHE NETHERLANDS ABSTRACT – Background and Objectives: Testosterone deficiency has been implicatedin the etiology of depression although there is an ongoing debate on the nature of thisassociation. There is a paucity of data about the psychological impact of hypogonadism ingenetic disorders associated with testosterone deficiency.Methods: A 57-year-old male is described who was referred for treatment resistantdepression. His history showed infertility and lowered testosterone. A selective literaturereview is given to clarify the patient’s clinical condition.Results: Cytogenetic analysis demonstrated a Robertsonian translocation betweenchromosomes 13 and 14 that accounted for his infertility. The psychopathological picturedid not meet the criteria for a major depressive disorder but was characterized by symp-toms of apathy or avolition. These symptoms were most probably aggravated by previouslong lasting treatment with antidepressants. Conclusions: Testosterone deficiency may be related to motivational deficits thatshould not be misunderstood for depressive illness. Apathy is probably an underestimatedside effect of antidepressants.Received 21 March 2008Revised 17 July 2008Accepted 22 July 2008196 WILLEM VERHOEVEN ET AL.IntroductionIn the sixties and seventies of the past cen-tury many studies have examined the chromo-somal contribution to male infertility. Report-ed frequencies of chromosomal abnormalitiesrange from 2.2% to 19.6% depending on theseverity of male infertility1. Since the intro-duction of modern in vitro fertilization tech-niques, it is common practice to performcytogenetic screening in patients with maleinfertility and chromosomal anomalies in upto 12% of cases are found of which theRobertsonian translocation 13;14 is the mostfrequent2-4. The majority of infertile maleshave normal levels of testosterone, LH andFSH. There is only one older case reportabout a slightly lower testosterone in apatient with this type of translocation5. Insome infertile patients a primary testicularfailure is present in which only low testos-terone levels are found6.It is well known that androgens like testos-terone are implicated not only in sexual func-tions, but are thought to be also involved inaggression, social ranking and mood,although the data are difficult to interpret7,8.With respect to mood, it is hypothesized thattestosterone modulates the activity of thehypothalamic pituitary adrenal axis9. Moststudies about the relationship between moodand testosterone have been performed inaging men. It is still unclear whether there is arelationship between lower testosterone andmajor depression. Psychological dysfunctionssuch as irritability, fatigue, decreased sexdrive, lack of motivation, and energy and areduced feeling of well being are found thatdo not meet the criteria for a categorical diag-nosis of major depression with or withoutmelancholia10-13.In male patients with oligozoospermiaand testosterone deficiency caused by acytogenetic abnormality, hypogonadism islife long present and therefore the psycho-logical consequences of low testosteronecan be hypothesized to have a major impacton the development as a whole. Reportsabout hypogonadism with a genetic causeon development and psychological func-tioning are lacking.In this case report, a male patient isdescribed who had been treated for a depres-sive illness during several decades and inwhom infertility due to a genetic abnormali-ty and low testosterone was demonstrated.These findings are discussed in relation tothe testosterone-depression debate. Case reportThe patient is a 57 year old male who wasreferred to the department of neuropsychiatryfor re-evaluation of long lasting therapyresistant mood disturbances. He was bornfrom non consanguine parents and had 3younger sibs. His family history showed nomental disorders. During infancy and devel-opment there were no major somatic prob-lems. His developmental history was charac-terized by a certain social withdrawal andlack of motivation in all domains. Althoughthe patient completed both elementary andhigh school, his professional career showed aplethora of unfinished educations and nondemanding jobs. From the age of 22 therewere complaints about feelings of inferiority,mood instability and problems in task com-pletion for which he visited several psycholo-gists and psychiatrists. In subsequent yearsthe patient had several short lasting relation-ships and sexual dysfunctions. He marriedaged 37 and he has a 12 years old son. At theage of 51 he was declared unable to work.Two years before, a diagnosis of bipolaraffective disorder was made elsewhere forwhich he was treated with carbamazepine,Lithium and citalopram. During subsequentyears treatment with various combinations ofmood stabilizers and antidepressants did notimprove his daily functioning and moodsymptoms. The last 3 years his daily treat-ment consisted of 1500mg Lithium (0.9mmol/l) and 1350mg (67mg/l) valproic acid.Six years ago he developed obesity andinsuline dependent diabetes mellitus type II,complicated by neuropathy that was con-firmed with electromyography as well as anincreased erectile dysfunction. Sildenafil wasineffective. Because of a low free testos-terone (4.4 nmol/l; normal range: 10-28nmol/l) and increased levels of LH (13,1 U/l;normal range: 2-9 U/l) and FSH (27,9 U/l;normal range:1,5-12 U/l), three years later adiagnosis of hypogonadism was made forwhich he was treated with testosterone oncebiweekly for 3 months without any effect onerectile function or general well being. Forhis diabetes mellitus the patient used insulinand oral antidiabetics.At admission, the patient complainedabout fatigue, irritability, loss of libido,erectile dysfunction, problems in task com-pletion and the inability to lead a self-serv-ing life. He presented with a submissive andpassive attitude, mental slowness and tired-ness. Neuropsychiatric examination by meansof a semi structured interview using the ele-ments of the Comprehensive PsychiatricRating Scale disclosed no major psychiatricdisorder. Anamnestic information revealedinfertility and his son was born after donorinsemination. Extensive neuropsychologicalassessment demonstrated a total IQ of 128(WAIS-III; verbal: 122; performal: 127), amild to moderate impairment of attention/con-centration with subsequent problems in thearea of executive functioning. These mildcognitive dysfunctions were found to beembedded in a personality pattern charac-terized by self-devaluation combined withheightened sensitivity for critical evaluation,experiential avoidance, and low persistence.Somatic examination showed, apart from aBMI of 35 (length: 1.82m; weight: 115kg;waist circumference: 120cm), no abnormali-ties and normal genitals. Laboratory datashowed slightly increased values for glucoseand HbA1c and a testosterone level at thelower margin of the reference values (11,0nmol/l; normal range: 9-38 nmol/l). Becauseof his infertility, cytogenetic analysis wasperformed that demonstrated a Robertsoniantranslocation between the chromosomes 13and 14 (figure 1) [karyotype: 45,XY, der(13;14) (q10;q10)].AVOLITION AND HYPOGONADISM 197Figure 1. Robertsonian translocation 45,XYder(13;14)(q10;q10).During the clinical observation period,mood stabilizing agents were graduallytapered off and his medication for the dia-betes mellitus was optimalized. At dis-charge the patient used insulin and oralantidiabetics and he reported an increasedlevel of activity and feeling of well being. Because of complete impotence, he under-went, after discharge, a second treatmentwith testosterone for 3 months that, however,was ineffective. At follow up after one year,the daily functioning of the patient was stillcharacterized by lower psychological vitali-ty, lack of motivation and irritability.DiscussionIn the here reported patient, referred fortreatment refractory depression, cytogeneticanalysis demonstrated a Robertsoniantranslocation between chromosomes 13 and14 associated with infertility due to oligo-zoospermia. His medical history mentioneda testosterone deficiency, possibly related tothe cytogenetic abnormality and aggravatedby the diabetes mellitus type II. After dis-continuation of all psychotropics, his dailyfunctioning improved and returned to thelevel he had before the prescription of anti-depressants and mood stabilizers. A secondtrial with testosterone did not improve hiserectile dysfunction neither his psychologi-cal functioning. In retrospect, his obesitywas aggravated by the use of antidepressantsand mood stabilizers that resulted in insulineresistance and diabetes mellitus. Moreover,his avolition and apathy increased due totreatment with antidepressants and conse-quently he was declared unable to work atthe age of 51. It cannot be ruled out that hislow testosterone levels have caused reducedinsulin sensitivity14.Based on his history and the assessment ofpsychopathology and psychological function-ing, a diagnosis of depressive disorder couldnot be established. In fact, his clinical condi-tion could better be accounted for by the term‘apathy’ or by the ‘syndrome of avolition’. Thesyndrome of apathy comprises lack of motiva-tion, diminished goal-directed cognition andreduced emotional concomitance of goal-directed behaviour15,16. It is often characterizedby life long passivity, low role activity, low selfesteem and low life satisfaction. Avolition is apsychological state characterized by severeproblems in willed action, typically presentingwith a general lack of desire, drive or motiva-tion to strive for meaningful goals, and relatedto executive dysfunctioning. Symptoms of apa-thy or dysexecutive functioning can be inducedor enhanced by antidepressants, especiallySSRI’s, and are reported in case series withchildren and adults17,18. In the epidemiologicalstudy by Van Geffen and coworkers, this phe-nomenon is listed as one of the 15 most fre-quently side effects reported by patients19.Since the isolation of testosterone in theearly thirties of the past century, this androgenhas been associated with mood disturbancesand subsequently used in the treatment of‘depression’20. During the past decades, sever-al placebo-controlled clinical trials with testos-terone have been performed in hypogonadalolder men, demonstrating antidepressant likeeffects in some but not all studies21. It shouldbe stressed, however, that these studies dealwith mild depression and that the effects areonly minimal. This can be illustrated by thestudy by Pope and coworkers who reported anantidepressant effect that was restricted to thenon-affective symptoms of the HamiltonDepression Rating Scale but not present on theBeck Depression Inventory22. The effects oftestosterone may therefore reflect the reversalof age related fatigue instead of a direct effectof this androgen on depression23. As stated by198 WILLEM VERHOEVEN ET AL.Amore, the relationship between testosteronedeficiency and psychological dysfunctionsmay be the result of an interaction betweenbiological and social changes and of the per-sonal ability to adapt to age-related changes12.In conclusion, symptoms of avolition andapathy are clinically relevant in hypogonadalmen and should not be automatically placed inthe expanding categorical concept of depres-sion. Since such symptoms can be worsened byantidepressants, especially SSRI’s, cliniciansshould be cautious in the prescription of thesecompounds, particularly in hypogonadal men. References1. Chandley AC. The chromosomal basis of humaninfertility. Br Med Bull 1979; 35: 181-186.2. Mau UA, Bäckert IT, Kaiser P, et al. Chromosomalfindings in 150 couples referred for genetic counsellingprior to intracytoplasmic sperm injection. Hum Reprod1997; 12: 930-937.3. Tuerlings JHAM, De France HF, Hamers A, et al.Chromosome studies in 1792 males prior to intracytoplas-mic sperm injection: the Dutch experience. Eur J HumGenet 1998; 6: 194-200.4. Peschka B, Leygraag J, Van der Ven K, et al. Type andfrequency of chromosome aberrations in 781 couplesundergoing intracytoplasmic sperm injection. Hum Reprod1999; 9: 2257-2263.5. Uccellatore F, Padova G, Squatrito S. Reproductivehormone studies in three subjects with a Robertsoniantranslocation. J Endocrinol Invest 1983; 6: 479-484.6. Bhasin S. Approach to the patient. Approach to theinfertile man. J Clin Endocrinol Metab 1995; 92: 1995-2004.7. Rubinow DR, Schmidt PJ. Androgens, brain, andbehavior. Am J Psychiatry 1996; 153: 974-984.8. Mazur A, Booth A. Testosterone and dominance inmen. Behav Brain Sci 1998; 21: 353-397.9. Rubinow DR, Roca CA, Schmidt PJ et al. Testosteronesuppression of CRH-stimulated cortisol in men. Neuropsy-chopharmacology 2005; 30: 1906-1912.10. Delhez M, Hansenne M, Legros JJ. Andropause andpsychopathology: minor symptoms rather than pathologi-cal ones. Psychoneuroendocrinology 2003; 28: 863-874.11. Shores MM, Moceri VM, Sloan KL, et al. Low tes-tosterone levels predict incident depressive illness in oldermen: effects of age and medical morbidity. J Clin Psy-chiatry 2005; 66: 7-1412. Amore M. Partial androgen deficiency and neuropsy-chiatric symptoms in aging men. J Endrocrinol Invest 2005;28: 49-54.13. Tostain JL, Blanc F. Testosterone deficiency: a com-mon, unrecognized syndrome. Nat Clin Pract Urol 2008; 5:388-396. 14. Kapoor D, Aldred H, Clark S, et al. Clinical and bio-chemical assessment of hypogonadism in men with type 2diabetes. Diabetes Care 2007; 30: 911-917.15. Marin RS. Differential diagnosis and classificationof apathy. Am J Psychiatry 1990; 147: 22-30.16. Marin RS. Apathy: a neuropsychiatric syndrome. JNeuropsychiatry Clin Neurosci 1991; 3: 243-253.17. Hoehn-Saric R, Lipsey JR, McLeod DR. Apathy andindifference in patients on fluvoxamine and fluoxetine. JClin Psychopharmacol 1990; 10: 343-345.18. Garland EJ, Baerg EA. Amotivational syndromeassociated with selective serotonin reuptake inhibitors inchildren and adolescents. Child Adolesc Psychopharmacol2001; 11: 181-186.19. Van Geffen ECG, Van der Wal SW, Van Hulten R, etal. Evaluation of patients’ experiences with antidepressantsreported by means of a medicine reporting system. Eur JClin Pharmacol 2007; 63: 1193-1199.20. Danziger L, Blank HR. Androgen therapy of agitateddepressions in the male. Med Ann DC 1942; 1: 181-183.21. Carnahan RM, Perry PJ. Depression in aging men.Drugs Aging 2004; 21: 361-376.22. Pope HG, Cohane GH, Kanayama G, et al. Testoste-rone gel supplementation for men with refractory depres-sion: a randomized, placebo-controlled trial. Am J Psy-chiatry 2003; 160: 105-111.23. Schmidt PJ, Berlin KL, Danaceau MA, et al. The effectsof pharmacologically induced hypogonadism on mood inhealthy men. Arch Gen Psychiatry 2004; 61: 997-1004.Address for correspondence:Prof. Dr. W.M.A. VerhoevenVincent van Gogh Institute for PsychiatryStationsweg 465803AC Venray, The Netherlands Phone: 0031.478527339Fax: 0031.478527339E-mail: wverhoeven@vvgi.nlAVOLITION AND HYPOGONADISM 199

Avolition in a patient with hypogonadism

Background and Objectives: Testosterone deficiency has been implicated in the etiology of depression although there is an ongoing debate on the nature of this association. There is a paucity of data about the psychological impact of hypogonadism in genetic disorders associated with testosterone deficiency. Methods: A 57-year-old male is described who was referred for treatment resistant depression. His history showed infertility and lowered testosterone. A selective literature review is given to clarify the patient's clinical condition. Results: Cytogenctic analysis demonstrated a Robertsonian translocation between chromosomes 13 and 14 that accounted for his infertility. The psychopathological picture did not meet the criteria for it major depressive disorder but was characterized by symptoms of apathy or avolition. These symptoms were most probably aggravated by previous long lasting treatment with antidepressants. Conclusions: Testosterone deficiency may be related to motivational deficits that should not be misunderstood for depressive illness. Apathy is probably an underestimated side effect of antidepressants

Avolition in a patient with hypogonadism

Abstract

Similar works

Full text

Available Versions

Erasmus University Digital Repository

EUR Research Repository

EUR Research Repository