Professor,
Department of Psychiatry,
University of British Columbia
Strategies to Improve Treatment Adherence for Patients with Major Depressive Disorder
Major Depressive Disorder (MDD) is one of the most common mental disorders in Hong Kong with a prevalence of 2.9%1. In spite of its substantial health burden, the utilisation of local mental health services is suboptimal. Notably, among patients dispensed with an antidepressant in outpatient clinic, 46% were reported to be non-adherence and were associated with a high rate of relapse and recurrence2. In a recent sharing, Prof. Raymond Lam highlighted the potential reasons for treatment non-adherence amongst patients with MDD and shared the strategies to improve treatment adherence in patients with MDD.
Factors to Consider in Antidepressant Selection
In the Canadian Network for Mood and Anxiety Treatments (CANMAT) depression guidelines 2016, pharmacological treatments for MDD are classified as first, second or third-line treatment3. Prof. Lam suggested that most of the newer antidepressants are first-line since they generally have good evidence on efficacy and tolerability.
In selecting first-line medication for MDD, there is no single medication which is the most effective for every patient. Thus, Prof. Lam advised considering both patient factors and medication factors in selecting medication. Patient factors include clinical symptoms exhibited, comorbidities, side effects to previous antidepressants and preference of the patient. On the other hand, as medications have differences in efficacy and tolerability, medication factors have to be considered. In addition to efficacy and tolerability, potential drug interaction, simplicity of use as well as the cost and availability of medication have to be taken into account3. Hence, Prof. Lam emphasised that selecting an antidepressant involves an individualised need assessment for each patient.
Reasons for Frustration for People Taking Antidepressants
Prof. Lam presented the findings of a survey involving 2,096 patients with MDD that a significant proportion (29.8%) of respondents with inadequate response to medication was frustrated (Figure 1). The results further revealed that the lack of efficacy and side effects were the major reasons for frustration, accounting for 59.3% and 19.7% of moderate-to-severe frustration respectively4. Also, feelings of frustration with medication would adversely impact treatment adherence and patient-physician relationship. 33.3% of patients indicated their frustration with their medication had contributed to the intention to quit their medications4. The findings have illustrated the importance of preventing patients from experiencing side effects in addition to optimising treatment efficacy.
Figure 1. Patient emotions regarding their medication for MDD4
The importance of shared decision making
In order to enhance adherence, it is important to prevent treatment-associated frustration amongst MDD patients. Hence, the shared decision making (SDM) exercise is advocated in the management of MDD. Prof. Lam mentioned that SDM is collaborative and takes both scientific evidence and patient’s values and preferences into consideration. The exercise helps preventing paternalism and making the best individualised care decisions.
In implementing the SDM exercise, establishing a strong therapeutic alliance, using empathy and collecting patient feedback have been proven to be effective in supporting patients to adhere with medication and hence improving clinical outcomes5. Notably, Prof. Lam outlined the applications of Frequency, Intensity, and Burden of Side Effect Ratings (FIBSER) in routine assessment which indicates the need of changing treatment based on the side effect-associated interference on patient’s daily activities6.
Tolerable Therapy for MDD
Prof. Lam presented the findings of a survey evaluating medication side effects on occupational functioning. Among the 164 patients with MDD, the 5 major medication side effects impairing work functioning identified were daytime sleepiness (74%), trouble sleeping (73%), headache (59%), anxiety/agitation (57%) and nausea/stomach upset (29%)7. Prof. Lam commented that it is important to minimise the medication side effects interfering with work functioning. He then quoted that desvenlafaxine is one of the medications with low rate of side effects.
The safety and tolerability profiles of desvenlafaxine were evaluated in a randomised control trial (RCT) by Clayton et al (2009). The result suggested that nausea was the most common treatment-related side effect, whereas the impact of the side effect was transient and generally mild, and would not impair work functioning. Moreover, the results of the subset fixed-dose study demonstrated that the discontinuation rate due to treatment-related adverse events between desvenlafaxine 50 mg group (n=317) and placebo group (n=636) was not significant (4.1% vs. 3.8% respectively, p>0.05, Figure 2)8.
Figure 2. Discontinuation rate of desvenlafaxine 50 mg versus placebo8
On the other hand, a patient-reported survey of 344 respondents aged 18-65 with mild to severe depression treated with an antidepressant demonstrated that weight gain was the adverse event most frequently (31%) rated as “extremely difficult to live with”, it was followed by unable to have erection (25%), difficulty reaching orgasm (24%), and tired during the day (21%, Figure 3)9. The results thus indicated that weight gain, sexual side effects and fatigue are the major treatment-related side effects needed to avoid from the patients’ perspective.
Figure 3. Adverse events rated as “extremely difficult to live with” by patients9
For the issue of weight gain, McIntyre et al (2015) reported a significant decrease in body weight upon 8-week desvenlafaxine treatment in all body mass index (BMI) subgroups of MDD patients (p<0.0001, Figure 4). However, no significant difference in weight between placebo and desvenlafaxine was observed in longer term10. The findings thus demonstrated that desvenlafaxine would effectively reduce depressive symptoms regardless of baseline BMI, with no adverse impact on body weight. “We need to select medications which have clinical data to support minimal weight gain during treatment, which is a major concern of our patients,” recommended Prof. Lam.
Figure 4. Weight change upon treatment with desvenlafaxine and placebo in BMI≤2510, LOCF: last observation carried forward
Besides weight gain, Prof. Lam noted that treatment-related sexual side effects are poorly reported in clinical trials. He further presented the findings of a meta-analysis of 63 RCTs assessing the harm of sexual dysfunction associated with second generation antidepressants in adult patients with MDD. The results suggested that desvenlafaxine is associated with lower risk of sexual side effects11. Moreover, in a Phase IV RCT involving 909 patients with MDD, the reported rates of sexual dysfunction were comparable between desvenlafaxine and placebo12. Therefore, findings in former trials suggested that desvenlafaxine is a tolerable therapy with low risk of major side effects concerned by patients with MDD.
Restore Functioning for MDD Patients
Prof. Lam addressed that all antidepressants help to control symptoms. Nonetheless, from the view of patients, restore functioning is more important than remission of symptoms. Hence, he advised to select medication which is more likely to restore functioning for MDD patients. Besides, he stated that certain symptoms of depression have greater impact on functioning. According to an analysis of the clinical data in the STAR*D study, sad mood and concentration problems had the highest unique associations with impairment (Figure 5)13.
Figure 5. Relative importance of depressive symptoms on overall impairment13
In examining the effects of antidepressants on occupational functioning, Dunlop et al (2011) conducted the first RCT with employed population with MDD. In the trial, 437 MDD patients were randomly allocated to receive desvenlafaxine 50 mg (n=291) or placebo (n=146) for 12 weeks. The results showed that desvenlafaxine was efficacious for treating MDD in gainfully employed patients. Essentially, the overall work impairment as reflected by Work Productivity and Activity Impairment (WPAI) scale of desvenlafaxine group was significantly improved as compared to placebo (-26.1±2.3 vs. -18.8±3.0, p=0.021)14.
Prof. Lam described a clinical trial by his team aiming to investigate the impact of antidepressants on neurocognitive and occupational functioning in employed patients with MDD. After 8 weeks of open-label desvenlafaxine treatment, patients showed significant improvements in depressive symptom, neurocognitive, and work functioning measures (Montgomery Asberg Depression Rating Scale [MADRS] response=77% and MADRS remission=49%). Remarkably, the results further showed that improvement in neurocognitive functioning with desvenlafaxine was associated with greater improvement in both mood and occupational outcomes. This hence suggested that addressing cognitive dysfunction may improve clinical and occupational outcomes in employed patients with MDD15.
Final Remarks
In summary of his sharing, Prof. Lam reminded that lack of efficacy and occurrence of side effects are the major reasons for frustration towards MDD treatments among patients, whereas feelings of frustration would adversely impact adherence. Thus, medications with lower risk of side effects including weight gain, sexual dysfunction and fatigue should be selected. In terms of treatment efficacy, patients value functional recovery over controlling symptoms. Particularly, treatments that specifically address fatigue and cognition offer patients the best chance for full functional recovery. Based on the clinical trial data presented, desvenlafaxine is demonstrated to be effective in restoring cognitive and occupational functioning for MDD patients with preferable safety and tolerability profiles. Last but not least, implementation of SDM exercise by clinicians would likely minimise the occurrence of adverse events and optimise treatment outcomes
References
1. Lam et al. Soc Psychiatry Psychiatr Epidemiol 2015; 50: 1379-88. 2. Yau et al. Brain Behav 2014; 4: 390-7. 3. Kennedy et al. Can. J. Psychiatry. 2016; 61: 540-60. 4. Mago et al. BMC Psychiatry 2018; 18: 33. 5. Parikh et al. Can. J. Psychiatry. 2016; 61: 524-39. 6. Wisniewski et al. J Psychiatr Pract 2006; 12: 71-9. 7. Lam et al. Depress Res Treat 2012; : 630206. 8. Clayton et al. CNS Spectr 2009; 14: 183-95. 9. Ashton et al. Curr Ther Res - Clin Exp 2005; 66: 96-106. 10. McIntyre et al. Prim Care Companion J Clin Psychiatry 2015; 17. 11. Reichenpfader et al. Drug Saf. 2014; 37: 19-31. 12. Clayton et al. J Clin Psychiatry 2015; 76: 562-9. 13. Fried et al. PLoS One 2014; 9: e90311. 14. Dunlop et al. J Clin Psychopharmacol 2011; 31: 569-76. 15. Lam et al. J Affect Disord 2016; 203: 55-61.
