The page number in the footer is not for bibliographic referencingwww.tandfonline.com/oemd 5

S Afr Fam Pract
ISSN 2078-6190       EISSN 2078-6204 

© 2016 The Author(s)

REVIEW

Introduction

Major depressive disorder (MDD) is a severe and debilitating 
condition1 that occurs in 8–15% of the global population2 while 
locally one out of every ten South Africans suffer from depressive 
episodes at some point in their lifetime.3 Moreover, almost 50% 
of patients diagnosed with MDD suffer from co-morbid anxiety 
disorders, e.g. panic disorder and generalised anxiety disorder 
(GAD).1 As such, the diagnosis of MDD is complex, involving a 
systematic process that must consider and evaluate a range of 
core symptoms.4 Although MDD is a chronic psychiatric disorder, 
most patients only seek medical care during acute depressive 
episodes of which the majority of cases are reported in general, 
and not psychiatric practice.5 Although the acute manifestation 
of symptoms typically prompts patients to consult medical 
professionals, the pharmacological treatment of MDD follows 
an intensive and chronic course that requires uninterrupted 
adherence for at least 4–12 months.6 This being said, it has been 
demonstrated that up to 80% of patients are noncompliant by 
either missing daily doses or withdrawing therapy altogether.7-9 
As such, in an attempt to support healthcare providers in 
addressing the challenges met when patients diagnosed with 
MDD fail to comply with treatment, the current paper aims to 
broaden our understanding of the clinical, social and economic 
consequences of, and reasons for, antidepressant nonadherence.

Getting the facts straight

• Globally, an estimated 16 million annual attempts at suicide 
result in nearly 800 000 deaths.10

• 11 million of these attempts are preceded by depressive 
episodes.11

• Patients diagnosed with MDD have an estimated 5–10 years 
decrease in life expectancy12 not only related to suicidal 

behaviour, but mostly due to comorbid cardio-metabolic 
disorders.13

• Only 10% of MDD patients receive adequate treatment.9

• Even with intensive pharmacological treatment, only 60–70% 
of patients achieve remission.14

The importance of antidepressant adherence

While drugs may be slow to act, humans are slower at 
learning

Although increasing evidence demonstrates MDD to be 
associated with disorders that adversely affect normal sleep 
architecture, the immune system and metabolic function15, 
most of the currently available antidepressants act by targeting 
monoamine transmission in the brain. However, due to its 
dependence on a gradual change in central monoamine 
function15 and cognitive neurocircuitry, antidepressants have a 
slow onset of action. On the other hand, novel evidence indicates 
that long-term emotional learning processes may play a key role in 
antidepressant action whereby patients need to re-establish the 
emotional meanings of previously negative response–outcome 
contingencies while being under the influence of antidepressant 
action.16 This highlights the potential of psychotherapy as an 
important add-on to drug-based treatment approaches.

Clinical example: Tom (pseudonym) was consulted at your practice 
in 2014 following a major depressive episode and was diagnosed 
with MDD. One of the most prominent factors that triggered his 
depression was conversations with his ex-wife that concerned 
their children. Although being in no position to change his 
reality, confrontations with his ex-wife constantly caused him to 
doubt his adequacy as a father. However, being a sufferer from 
MDD, he was unable to realise that during the dialogues with 
his wife, neither he, nor his suitability as a father was the subject 

Abstract

Major depressive disorder (MDD) is an insidious disease and affects up to 15% of the global population. Although MDD responds 
to a wide range of pharmacological treatment options, a number of factors, i.e. not adhering to treatment for at least 4–12 months, 
contribute to antidepressants not being highly effective. In an attempt to aid clinicians in improving the adherence rates among 
MDD patients, the current paper will divulge in more detail the possible explanations of why individuals with MDD find it difficult 
to adhere to prescribed regimens.

South African Family Practice 2016; 58(4):5-8
 
Open Access article distributed under the terms of the 
Creative Commons License [CC BY-NC-ND 4.0] 
http://creativecommons.org/licenses/by-nc-nd/4.0

Mind your state: Insights into antidepressant nonadherence
De Wet Wolmarans1, Sarel J. Brand1

1Centre of Excellence for Pharmaceutical Sciences, Division of Pharmacology, Faculty of Health Sciences,  
North-West University, Potchefstroom
Corresponding author, email: dewet.wolmarans@nwu.ac.za



S Afr Fam Pract 2016;58(4):5-86

The page number in the footer is not for bibliographic referencingwww.tandfonline.com/oemd 6

of discussion, but that the best interests of their children were 
at stake. While being treated for MDD, Tom gradually learned 
that although the subject of these conversations fundamentally 
remained the same and that they would always remind him of 
his life before the divorce, they had no emotional meaning other 
than providing a stable arrangement for their children.

What is remission worth to you?

It has repeatedly been demonstrated that nonadherence to 
antidepressant treatment results in poor clinical17, social18 and 
economic19 outcomes. As such, patients not adhering to at 
least four to twelve months of uninterrupted antidepressant 
use are at an increased risk for symptom relapse, treatment 
resistance and hospitalisation.7, 20 Over time this translates to 
higher rates of unemployment, marital discord and unstable 
social relationships.21 Furthermore, although adherent patients 
incur significantly higher drug costs compared to noncomplying 
individuals22, their total expenditure based on all depression-
related medical interventions is often much lower.7

Why is treatment adherence so difficult?

The personal character of a depressed mood

Considering that depression is at its core a complex emotional 
condition that is not easily defined and subject to personal 
bias, various studies have aimed to elucidate the role of patient 
experience in the treatment of MDD.23 Indeed, individuals that 
present with symptoms of MDD are often unconvinced that 
the feelings they experience, i.e. anhedonia, carelessness or 
fatigue, may be traits of a larger psycho-biological disorder that 
necessitates pharmacological intervention.24 As such, patients 
will often avoid seeking medical attention, and they regularly 
find it difficult to commit to treatment once they do consult a 
healthcare professional. A number of social and personal factors 
may contribute to patients not choosing to accept the reality of 
their mood state and being hesitant to disclose their emotions. 
Hence, feelings of vulnerability to interpersonal scrutiny and 
stigmatisation, thinking that partners or next of kin will set 
unrealistic goals for treatment, and knowing themselves better 
than anyone else often lead these individuals to believe that they 
are able to self-regulate their behaviour.23

Trust is hard to earn

The concept of trust is perhaps the most important factor 
determining whether patients will adhere to treatment.25 
With respect to MDD, trust can broadly be conceptualised on 
two levels, i.e. 1) accepting the neurobiological nature of the 
condition and believing that adhering to treatment will result in 
symptom attenuation; and 2) trusting healthcare practitioners 
to manage the clinical prognosis of the condition. Indeed, the 
slow onset of action of antidepressants and sometimes severe 
nature of their side-effects as well as the fact that treatment 
adherence is not a guarantee to achieve symptom remission lead 
to 60–80% of patients being hesitant about the likelihood of a 
positive outcome with continuous drug treatment.23, 26 Moreover, 
recent studies highlighted the impact of distrustful relationships 
between MDD patients and their clinicians in treatment 

nonadherence.24, 25 Particularly during phases of nonadherence, 

patients have reported that they deliberately avoid therapists 

for three main reasons, i.e. 1) they do not believe that their 

clinicians are competent to appreciate their own perceived 

need for change; 2) the prescribing clinician will often argue for 

continuing or augmenting the current treatment regimen; and 

3) they experience consultations with their clinicians as taxing 

intellectual debates concerning the necessity to make changes 

to current, and in their view, failing interventions.23 Interestingly, 

these feelings are exacerbated by the differing perceptions of 

psychiatrists and general practitioners regarding MDD.5 Also, 

as patients often switch between clinicians, inter-professional 

differences in opinion and prescribing patterns27 contribute 

to patients not trusting their therapists with managing their 

disease.5, 23

Fostering patient patients: Intervening on their behalf

Taken from the above, clinicians can intervene on various levels 

to improve antidepressant adherence:

• Accept that MDD is intrinsically founded in both the 

psychological and biological domains. As such, it will be 

difficult to convince patients that they will be cured simply by 

prescribing antidepressants.

• Personal bias and self-regulation will more often than not be 

part of discussions between clinician and patient. Essentially, it 

is not a case of your patients trying to know better, but rather 

informing you about how they feel. In fact, pertaining to mood 

disorders, conversation is the only means of diagnosis and 

clinical follow-up.

• It’s all about trust. From the first consultation, be honest about 

the complexity of MDD and the uncertainty of treatment 

outcome. Schedule longer first appointments that allow 

time for careful diagnosis and accept that once you initiate 

treatment, a commitment to follow up must be made.

• Importantly, rather refer than desert. Treating patients with 

psychiatric illness, especially conditions that may trigger 

suicidal behaviour, is different from alleviating pain or curing 

infection. It requires time, an ability to listen and the assurance 

of being there.

Conclusion

MDD is a highly heterogeneous and complex psycho-biological 

mood disorder that necessitates chronic, uninterrupted 

pharmacological treatment. However, a number of factors 

contribute to the fact that up to 80% of patients diagnosed with 

MDD do not adhere to drug treatment. Key to this is the relative 

uncertainty of treatment outcome and a lack of trust between 

patients and their therapists. While patients have a responsibility 

to commit to therapist-initiated interventions, clinicians are 

challenged to change their perceptions of MDD and to accept 

that treating mood disorders involves a unique and singular 

approach.



S Afr Fam Pract 2016;58(4):5-88

The page number in the footer is not for bibliographic referencingwww.tandfonline.com/oemd 8

References

1. Kessler RC, et al. Lifetime prevalence and age-of-onset distributions of mental 
disorders in the World Health Organization’s world mental health survey 
initiative. World Psychiatry, 2007;6(3):168–176.

2. Andrade L, et al. The epidemiology of major depressive episodes: Results from 
the International Consortium of Psychiatric Epidemiology (ICPE) Surveys. 
International Journal of Methods in Psychiatric Research, 2003;12(1):3–21.

3. Tomlinson M, et al. The epidemiology of major depression in South Africa: 
Results from the South African Stress and Health study. South African Medical 
Journal, 2009;99(5):368–373.

4. American Psychiatric Association. Diagnostic and statistical manual of mental 
disorders. Vol. 5. 2013, Washington, DC: American Psychiatric Association.

5. Davidsen AS, Fosgerau CF. What is depression? Psychiatrists’ and GPs’ 
experiences of diagnosis and the diagnostic process. International Journal of 
Qualitative Studies on Health and Well-being, 2014;9.

6. Geddes JR, et al. Relapse prevention with antidepressant drug treatment in 
depressive disorders: A systematic review. Lancet, 2003;361(9358):653–661.

7. Ho SC, et al. Clinical and economic impact of non-adherence to antidepressants 
in major depressive disorder: A systematic review. Journal of Affective Disorders, 
2016;193:1–10.

8. Keller MB, et al. Optimizing outcomes in depression: Focus on antidepressant 
compliance. International Clinical Psychopharmacology, 200217(6):265–271.

9. Epstein I, Szpindel I, Katzman MA. Pharmacological approaches to manage 
persistent symptoms of major depressive disorder: rationale and therapeutic 
strategies. Psychiatry Research, 2014;220(S1);S15–S33.

10. World Health Organization ( WHO), Preventing suicide: A global imperative. 
2014;92.

11. Trivedi MH, Daly EJ. Treatment strategies to improve and sustain remission 
in major depressive disorder. Dialogues in Clinical Neuroscience, 
2008;10(4):377–384.

12. Ciechanowski PS, Katon WJ, Russo JE. Depression and diabetes: Impact of 
depressive symptoms on adherence, function, and costs. Archives of Internal 
Medicine, 2000; 160(21):3278–3285.

13. McIntyre RS, et al. The effect of antidepressants on glucose homeostatis and 
insulin sensitivity: Synthesis and mechanisms. Expert Opinion on Drug Safety, 
2006;5(1):157–168.

14. Gaynes BN, et al. What did STAR*D teach us? Results from a large-scale, 
practical, clinical trial for patients with depression. Psychiatric Services, 
2009;60(11):1439–1445.

15. Willner P, Scheel-Krüger J, Belzung C. The neurobiology of depression 
and antidepressant action. Neuroscience and Biobehavioral Reviews, 
2013;37(10):2331–2371.

16. Roiser JP, Elliott R, Sahakian BJ. Cognitive mechanisms of treatment in 
depression. Neuropsychopharmacology, 2012;37(1):117–136.

17. Alekhya P, et al. Adherence to antidepressant therapy: Sociodemographic factor 
wise distribution. International Journal of Pharmaceutical and Clinical Research, 
2015;7(3):180–184.

18. Kessler RC, et al. Social consequences of psychiatric disorders, II: Teenage 
parenthood. American Journal of Psychiatry, 1997;154(10):1405–1411.

19. Osterberg L, Blaschke T. Adherence to medication. New England Journal of 
Medicine, 2005;353(5):487–497.

20. Liu X, Tepper PG, Able SL. Adherence and persistence with duloxetine and 
hospital utilization in patients with major depressive disorder. International 
Clinical Psychopharmacology, 2011;26(3):173–180.

21. Kessler RC, et al. Social consequences of psychiatric disorders, I: Educational 
attainment. American Journal of Psychiatry, 1995;152(7):1026–1032.

22. White TJ, et al. Economic Impact of Patient Adherence with Antidepressant 
Therapy Within a Managed Care Organization. Disease Management and Health 
Outcomes, 2003;11(12):817–822.

23. Buus N. Adherence to anti-depressant medication: A medicine-taking career. 
Social Science and Medicine, 2014;123:105–113.

24. McMullen LM, Herman J. Women’s accounts of their decision to quit taking 
antidepressants. Qualitative Health Research, 2009;19(11):1569–1579.

25. Anderson C, Roy T. Patient experiences of taking antidepressants for depression: 
A secondary qualitative analysis. Research in Social and Administrative 
Pharmacy, 2013; 9(6):884–902.

26. Van Geffen ECG, et al. The decision to continue or discontinue treatment: 
Experiences and beliefs of users of selective serotonin-reuptake inhibitors in 
the initial months-A qualitative study. Research in Social and Administrative 
Pharmacy, 2011;7(2):134–150.

27. Davies NM, et al. Physicians’ prescribing preferences were a potential instrument 
for patients’ actual prescriptions of antidepressants. Journal of Clinical 
Epidemiology, 2013;66(12):1386–1396.