The Diagnostic and Statistical Manual of Mental Disorders fifth edition, distinguishes between the following forms of depression:³

• Major depressive disorder (MDD)
• Persistent depressive disorder, formerly known as dysthymia
• Disruptive mood dysregulation disorder
• Premenstrual dysphoric disorder
• Substance/medication-induced depressive disorder
• Depressive disorder due to another medical condition
• Unspecified depressive disorder.

According to the World Health Organization, MDD will be ranked as the leading cause of the burden of disease worldwide by 2030.³

Signs, symptoms, and severity

Signs and symptoms of MDD include persistently low or depressed mood, anhedonia or decreased interest in pleasurable activities, feelings of guilt or worthlessness, lack of energy, poor concentration, appetite changes, psychomotor retardation or agitation, sleep disturbances, or suicidal thoughts.³

MDD is classified as mild (five symptoms), moderate (six to seven symptoms), and severe (eight to nine symptoms). Severe depression is associated with a high risk of suicide.⁴

About 30% of patients with MDD have severe disease, which is associated with difficulties in achieving treatment response (50% or greater decrease in depression severity) and remission (a Hamilton Depression Rating Scale of ≤7).⁵

Furthermore, ~75% of people with MDD also have a co-occurring anxiety disorder, exacerbating their symptoms, and further complicating recovery (defined as sustained remission during the maintenance phase, meaning that the episode has ended).⁵

Treatment of MDD can be divided into three phases:⁵

• Acute: The goal is to achieve remission, which is defined as the resolution of symptoms.
• Continuation: The aim is to preserve remission and prevent relapse, which is defined as the return of symptoms during the acute or continuation phase and is considered part of the same episode.
• Maintenance: The aim is to prevent recurrence, which is defined as the return of symptoms and is considered a new, distinct episode.

The 2023 American College of Physicians’ living clinical guideline for the non-pharmacologic and pharmacologic treatments of adults in the acute phase of MDD, recommends monotherapy with either cognitive behavioural therapy or a second-generation antidepressant as initial treatment. Recommended first-line pharmacological treatment includes selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs).

Recommended second-line treatment strategies include:⁵

• Switching to another second-generation antidepressant
• Switching from a second-generation antidepressant to a non-pharmacologic treatment
• Augmenting a second-generation antidepressant with non-pharmacologic treatment or additional pharmacologic treatment (such as a different second-generation antidepressant, atypical antipsychotics, psychostimulants, or the anxiolytic buspirone).

Treatment should be personalised and based on potential benefits, harms, adverse effect profiles, cost, feasibility, patients' specific symptoms (such as insomnia, hypersomnia, or fluctuation in appetite), comorbidities, concomitant medication use, and patient preferences.⁵

Efficacy of antidepressant drug classes

The 2018 landmark head-to-head study by Cipriani et al, showed that agomelatine (melatonin agonist and selective serotonin antagonist), amitriptyline (tricyclic antidepressant), escitalopram (SSRI), mirtazapine  (tetracyclic antidepressant), paroxetine (SSRI), venlafaxine (SNRI), and vortioxetine (SSRI) were more effective than other antidepressants.⁶

A meta-analysis comparing SSRIs and SNRIs using intention-to-treat analyses showed that remission rates were 48.5% for SNRIs and 41.9% for SSRIs. Per protocol rates of remission were 66.6% for SNRIs and 53.9% for SSRIs. There were statistically significant benefits observed in total remission with treatment with SNRIs compared to SSRIs for both intention-to-treat data (odds ratio [OR] 1.27) and per protocol data (OR 1.56).⁷ 

The cost of having MDD

MDD severely impacts the quality of life (QoL) of patients and their caregivers. Apart from the emotional, social, and economic impact of MDD on patients and their caregivers, healthcare costs attributable to the management of MDD are extremely high. In 2020, direct medical and pharmaceutical costs attributable to the treatment of MDD in the United States were estimated to be ~$36b, while suicide-related costs came to ~$13b, and effects on workplace productivity to ~$70 billion.⁵

Numerous studies have shown that the use of generics in the treatment of patients with chronic diseases can substantially reduce out-of-pocket expenditure on pharmacotherapy, which may also improve adherence to treatment.⁸

A 2017 observational study among patients with chronic diseases showed that 93% of patients using a generic, and 87% of those using a brand-name product, believed that their symptoms were effectively controlled. No significant difference (9% generics vs 10% brand-name) was observed in reported adverse events.⁸

Furthermore, 82% and 77% of patients were adherent to generics vs brand-name products, respectively. Generics were associated with significantly lower costs compared to their brand-name counterparts.⁸

Despite these and similar findings, criticism is often levelled against generics regarding bioequivalence, which some say may impact long-term outcomes in patients – especially those with psychiatric disorders. To put this criticism to the test, Unterecker et al compared for example generic versus brand-name venlafaxine.⁹

Venlafaxine was the first SNRI to be approved for the treatment of MDD by the American Food and Drug Administration (1993), followed by approval (1997) of a once-daily micro-encapsulated extended-release (XR) formulation.¹⁰

In South Africa, venlafaxine is approved for the treatment of depression (which includes anxiety associated with depression), severe and persistent anxiety (generalised anxiety disorder), and social anxiety disorder also known as social phobia.¹¹

Venlafaxine IR has a five-hour half-life, while venlafaxine XR has a longer half-live (11 hours). Venlafaxine disproportionately inhibits serotonin and norepinephrine reuptake, with a 30-fold higher affinity for serotonin. It sequentially inhibits serotonin reuptake before nor-epinephrine. Initial side effects (headaches, nausea) are serotonin-related, while higher doses cause both serotonin and nor-epinephrine effects (activation, dry mouth). At high doses, it may also inhibit dopamine reuptake.¹⁰

Unterecker et al found no difference in dose-corrected serum concentrations between generic and brand-name venlafaxine, concluding that the generic formulation was safe and effective.⁹

Conclusion

Depression, anxiety, or substance use disorder affect one in three South Africans, but only ~22% of diagnosed individuals seek treatment due to resource constraints, stigma, and cultural attitudes. Antidepressants are effective in managing MDD, which is associated with a high risk of suicide as well as emotional and economic costs. Cost-effective treatment options like generics have the potential to reduce out-of-pocket expenses and improve adherence, as shown in an observational study. Despite concerns about bioequivalence differences, a study on venlafaxine revealed no disparity in serum concentrations between generic and brand-name formulations.

References

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5. Qaseem A, Owens DK, Etxeandia-Ikobaltzeta I, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Annals of Internal Medicine, 2023.
6. Cipriani A, Furukawa TA, Salant G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet, 2018.
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8. Das M, Choudhury S, Maity S, et al. Generic versus branded medicines: An observational study among patients with chronic diseases attending a public hospital outpatient department. J Nat Sci Biol Med, 2017.
9. Unterecker S, Proft F, Riederer P, et al. The comparison of brand-name and generic formulations of venlafaxine: a therapeutic drug monitoring analysis. Ther Drug Monit, 2014.
10. Sansone RA, Sansone LA. Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison. Innov Clin Neurosci, 2014.
11. Patient Information. Illovex [Internet]. Available at: https://www.mydynamics.co.za/wp-content/uploads/2022/02/Illovex-XR-PIL-B2952.pdf