• Users Online: 86
  • Print this page
  • Email this page

Table of Contents
Year : 2019  |  Volume : 33  |  Issue : 1  |  Page : 53-54

Hypothesis for mechanism of sex differences in depression

Department of Psychiatry, Cardinal Tien Hospital, Taipei, Taiwan

Date of Submission28-Dec-2018
Date of Decision12-Jan-2019
Date of Acceptance14-Jan-2019
Date of Web Publication28-Mar-2019

Correspondence Address:
Jie- Yu Chuang
No. 362, Zhongzheng Road, Xindian District, New Taipei City 23148
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/TPSY.TPSY_11_19

Rights and Permissions

How to cite this article:
Chuang JY. Hypothesis for mechanism of sex differences in depression. Taiwan J Psychiatry 2019;33:53-4

How to cite this URL:
Chuang JY. Hypothesis for mechanism of sex differences in depression. Taiwan J Psychiatry [serial online] 2019 [cited 2020 Oct 31];33:53-4. Available from: http://www.e-tjp.org/text.asp?2019/33/1/53/255139

Depression is one of the most debilitating disorders affecting millions of people worldwide. However, some mystery remains in the etiology and treatment of depression. One of the unveiled mysteries is the mechanism and extent of sex differences in depression. An obvious sex difference in depression has three evidences as follows: (A) The incidence of depression for girls rises from age 11 to 13 years until by the age of 15 years is one of the most robust findings in psychiatric epidemiology revealing that females are twice as likely to suffer from depression than males[1]. (B) Men are more liable to have persistent depression, whereas women tend to suffer from a more episodic disorder[2]. (C) Depressed men are also more likely to commit suicide[3] and to abuse substances[4] than depressed women.

Knowing the overt sex difference of depression in incidence and symptoms, I suggest that sex differences in depression also possibly have its psychophysiological mechanism affecting treatment choices. However, treatment guidelines of depression do not take sex differences into consideration.

Current evidence indicate differences in inflammatory profiles[5], molecular signatures, and treatment responses toward antidepressants in depressed men and women[6]. Based on the above-noted findings, I hereby propose the external/internal model (E/I Model) for the sex difference in depression, i.e., more pronounced impairment in response to external stimuli (e.g., social interaction) in depressed women; and more conspicuous abnormality responding to internal thought (e.g., self-contemplation) in depressed men. Consequently, sex-specific depression treatment should be implemented, such as interpersonal therapy in women and meditation in men.

  Origin and Foundation of the Hypothesis Top

Etiology of depression

Depression is a multifactorial disorder without a specific etiologic pathway or causal relationship identified. As a result, etiology of depression is often assumed by analysis of risk factors. Using data from more than a 1,000 twins born between 1940 and 1974, the investigator found that deficiencies in caring relationships and interpersonal loss are more related to the etiology of female depression, whereas failure to achieve expected instrumental goals and lowered self-worth are more related to male depression[7]. Indeed, social stress is closely related to female depression, whereas low self-esteem is more likely to be related to male depression[7]. Since the social relationship is more related to external stimuli, whereas goals and self-esteem are more associated with internal stimuli, this finding can be seen as supporting evidence of the proposed E/I Model.

Effect of depression

Recent studies point toward distinct[8], and even opposite changes in the genetic expressions of depressed men and women[6]. Based on the findings, I suggest that treatments which boost immune function (a function which mainly involves responses toward external stimuli) might be more appropriate for depressed women than men[6]. Indeed, women are found to be more vulnerable to depression-causing effects of inflammation than men[5].

Early in adolescence, depression has been found to exert different effects in the brains of boys and girls[9]. Interestingly, brain regions showing sex-divergent brain effects are located within the default network (a network involving in internally-directed thought) with boys showing more prominent changes than girls[9].

  Treatment of Depression Top

It is controversial whether sex differences exist in the treatment response of depression. For example, some studies report different treatment responses exist toward antidepressants in depressed men and women[6], whereas current evidence indicates no significant sex difference in response to cognitive behavioral therapy. However, the content of psychotherapy has not been addressed in the comparison between different sexes[10]. Presumably, depressed men and women might respond differently toward different contents (e.g., social interaction training versus meditation).


Depression exerts sex-specific effects with more pronounced impairment in response to external stimuli (e.g., social interaction) in women and internal thought (e.g., self-contemplation) in men. Consequently, sex-specific depression treatment should be implemented, such as interpersonal therapy in women and meditation in men.

The biological basis of this E/I Model for the sex differences in depression remains obscure.

Empirical testing for the hypothesis

Virtual reality (VR) provides an immediately available life-sized environment of consistent quality for people to make repetitive new learning for the benefit of their psychological well-being which might be nearly impossible to recreate in real life[11]. Application of VR in depression study is suggested. For VR hardware, NVIDIA graphic card (www.nvidia.com) and Unreal Engine four (www.unrealengine.com) will be used to build up the stimulating environment. Two types of VR treatment will be implemented:

  • The external treatment

In a virtual park, the participant will have to interact with a child avator with sex-neutral voice impossible to be identified as a boy or girl. Encouragement will be given by the child.

  • The internal treatment

The participant will have to complete a five min mindfulness exercise with guidance provided again by a child with sex-neutral voice in a virtual park.

Adults meeting DSM-V criteria for current major depressive disorder, aged between 21 and 65 years will be included in the study with the exclusion criteria of psychotic disorder, organic brain disease, high risk of self-harm or suicide, and current substance misuse. Participants will then be randomly assigned to one-month weekly treatment with an equal number of male and female patients to three groups: to receive (A) the external, (B) the internal, and (C) traditional cognitive behavioral therapy.

Before the first treatment session, the VR environment and treatment task will be introduced by an instructor. Assessment with Hamilton Depression Rating Scale 21 (HDRS21) for depression will be done in the baseline, right after the final treatment session, and 1 month after the final treatment session as a primary outcome measure.

The hypothesis is that VR treatment might be equally effective for depression as compared to traditional cognitive behavioral therapy. Moreover, the external VR treatment may be more beneficial for depressed women, whereas the internal VR treatment might work better in depressed men.

Therapies suggested in the hypothesis

Depressed women should receive treatment focusing on external stimuli (e.g., interpersonal psychotherapy), whereas depressed men should receive treatment focusing on internal thought (e.g., mindfulness-based cognitive therapy).

Interpersonal psychotherapy is a time-limited (12–16 weeks) treatment with three phases: beginning, middle, and end. The therapist identifies the interpersonal context of depression in the beginning phase (e.g., end of a relationship), then in the middle phase, the therapist uses specific strategies to deal with the problem areas (e.g., to encourage taking appropriate social risks in a new relationship), and finally in the end phase, the therapist reviews the patient's considerable accomplishments during the treatment[12].

Mindfulness-based cognitive therapy teaches patients to observe their thoughts and feelings through the repeated practise of intentionally returning attention to a neutral object (e.g., breath or body sensations) in the present moment. Patients are taught to cultivate direct experiential awareness, together with an attitude of nonjudgmental acceptance, toward whatever is present. The therapy enables patients to see more clearly when negative and ruminative responses are being triggered and allows them to distract from such patterns of thought, seeing them as mental events, rather than necessarily valid reflections of reality[13].

Hopefully, this sex-divergent treatment strategy might result in improved prognosis. However, it should be noted that this hypothesis needed to be tested in more studies. (The author declares that she conceived and developed the hypothesis.)

  Financial Support and Sponsorship Top


  Conflicts of Interest Top

There are no conflicts of interest.

  References Top

Cyranowski JM, Frank E, Young E, Shear MK: Adolescent onset of the gender difference in lifetime rates of major depression: a theoretical model. Arch Gen Psychiatry 2000; 57: 21-7.  Back to cited text no. 1
Dunn V, Goodyer IM: Longitudinal investigation into childhood- and adolescence-onset depression: psychiatric outcome in early adulthood. Br J Psychiatry 2006; 188: 216-22.  Back to cited text no. 2
Morgan JK, Shaw DS, Olino TM, et al.: History of depression and frontostriatal connectivity during reward processing in late adolescent boys. J Clin Child Adolesc Psychol 2016; 45: 59-68.  Back to cited text no. 3
Marcus SM, Young EA, Kerber KB, et al.: Gender differences in depression: findings from the STAR*D study. J Affect Disord 2005; 87: 141-50.  Back to cited text no. 4
Bekhbat M, Neigh GN: Sex differences in the neuro-immune consequences of stress: focus on depression and anxiety. Brain Behav Immun 2018; 67: 1-2.  Back to cited text no. 5
Seney ML, Huo Z, Cahill K, et al.: Opposite molecular signatures of depression in men and women. Biol Psychiatry 2018; 84: 18-27.  Back to cited text no. 6
Kendler KS, Gardner CO: Sex differences in the pathways to major depression: a study of opposite-sex twin pairs. Am J Psychiatry 2014; 171: 426-35.  Back to cited text no. 7
Labonté B, Engmann O, Purushothaman I, et al.: Sex-specific transcriptional signatures in human depression. Nat Med 2017; 23: 1102-11.  Back to cited text no. 8
Chuang JY, Hagan CC, Murray GK, et al.: Adolescent major depressive disorder: neuroimaging evidence of sex difference during an affective go/No-go task. Front Psychiatry 2017; 8: 119.  Back to cited text no. 9
Weissman MM: Treatment of depression: men and women are different? Am J Psychiatry 2014; 171: 384-7.  Back to cited text no. 10
Freeman D, Reeve S, Robinson A, et al.: Virtual reality in the assessment, understanding, and treatment of mental health disorders. Psychol Med 2017; 47: 2393-400.  Back to cited text no. 11
Markowitz JC, Weissman MM: Interpersonal psychotherapy: principles and applications. World Psychiatry 2004; 3: 136-9.  Back to cited text no. 12
Kenny MA, Williams JM: Treatment-resistant depressed patients show a good response to mindfulness-based cognitive therapy. Behav Res Ther 2007; 45: 617-25.  Back to cited text no. 13

This article has been cited by
1 Interpersonal therapy group for middle-aged depressive patients: A pilot study
Chan-Hen Tsai,Chiung-Wen Chang,Hui-Ying Lee,Shih-Ming Li
Taiwanese Journal of Psychiatry. 2019; 33(4): 219
[Pubmed] | [DOI]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
   Origin and Found...
   Treatment of Dep...
   Financial Suppor...
   Conflicts of Int...

 Article Access Statistics
    PDF Downloaded140    
    Comments [Add]    
    Cited by others 1    

Recommend this journal