Understanding Depression: Risk Factors and Evolving Treatments

Depression affects approximately 5% of adults globally, explained Mei T. Liu, PharmD, BCPP, clinical assistant professor, Ernest Mario School of Pharmacy, Rutgers University, during a presentation at the American Society of Health-System Pharmacists (ASHP) Pharmacy Futures 2024 in Portland, Oregon. Depression is also the leading cause of disability and illness worldwide.

“In 2020, a survey indicated that 18.4% of the US adult population has been diagnosed with depression,” Liu said during the ASHP presentation. “Since the COVID-19 pandemic, we have also seen an increase in the number of psychiatric diagnoses recorded, and also an increased incidence of substance use disorder [SUD] as well.”

During the pandemic, loneliness was identified as a significant factor contributing to the development of depression, as well as a contributing factor to an increased risk of suicide.

“In particular, we do find that in women, young adults, or patients with a lower educational level, these individuals have higher risk factors that make them more vulnerable to depression,” Liu said. “The other thing about depression is that it's more than just a mental illness.”

Liu explained further that depression has a bidirectional relationship, meaning that it can be a risk factor for certain medical conditions, such as diabetes and heart disease, and those same medical conditions can also be a risk factor for depression.

“Patients with depression may also be more likely to develop [SUD] to self-medicate,” Liu said.

According to the DSM-5 criteria, for patients to be diagnosed with major depressive disorder (MDD), they typically have to have at least 5 or more of the following symptoms within the same 2 week period, with at least 1 of the symptoms being either depressed mood or diminished interest or pleasure in activities:

• Depressed mood
• Diminished interest or pleasure in activities
• Change in weight or appetite
• Sleep disturbance
• Psychomotor agitation or retardation
• Fatigue or loss of energy
• Feelings of worthlessness or excessive or inappropriate guilt
• Diminished ability to think or concentrate, or indecisiveness
• Recurrent thoughts of death, suicidal ideation, or a suicide attempt

Additionally, Liu noted that to be diagnosed with MDD, patients should also have a decline in their function compared to baseline.

“[Before diagnosing a patient with MDD,] we should also rule out medical causes, medication [adverse events], or substance-induced non-depression symptoms,” Liu said. “When you look at some of the criteria, such as change in sleep, change in appetite, psychomotor agitation, or retardation, we still see wide differences in how the patients may be presenting with depression.”

Liu explained that when some patients are depressed, they may present as anxious or unable to speak, or they may lose their appetite and fidget frequently.

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“Then we have patients that basically sleep all day, and they don't want to get out of bed and are not motivated,” Liu said. “A lot of times by looking at the patient's symptoms that they exhibit, we try to pick a pharmacotherapy that potentially can help counteract their particular symptoms.”

The cause of depression can be multifactorial, according to Liu. But based on established pathophysiology for depression, there are 2 factors that are more established and also serve as a basis for most of the antidepressant treatments currently on the market. Those factors include the monoamine hypothesis and neuroactive steroids.

“For the monoamine hypothesis, many may be familiar with it,” Liu said. “It's kind of centralized on the potential deficiency of neurotransmitters, such as serotonin, norepinephrine, and dopamine, which is why, when you look at most of the antidepressants on the market, their mechanism of actions revolve around those 3 main neurotransmitters.”

Neuroactive steroids are a new and upcoming area that have shown particular benefit for the treatment of postpartum depression, according to Liu.

“The particular neuroactive steroid allopregnanolone [Zulresso; Sage Therapeutics, Inc] is a steroid that they find in patients under chronic stress, in patients with MDD, and also in patients with postpartum depression. [For these patients,] there is potentially a lower level of that particular neuroactive steroid,” Liu said. “Therefore, by supplementing it, we can potentially help treat some of the depression symptoms patients may exhibit.”

Two additional areas of interest for the pathophysiology of depression include brain-derived neurotrophic factor and gut microbiota, according to Liu. However, these areas have been investigated to a lesser degree than the monoamine hypothesis and neuroactive steroids.

Furthermore, Liu explained that despite ongoing efforts to investigate and understand the pathophysiology of depression, there still remains a need for additional treatment options due to the diverse and multifactorial nature of the condition.

“Even though we have a lot more diverse options on the market today, one thing that we see is that there's still not quite enough [treatments available],” Liu said. “Ultimately, we have to recognize that for patients who develop depression, the causes are multifactorial, so, based on the biopsychosocial model of psychiatric disorders, patients might develop depression for biological or genetic reasons, it could be psychological, or it could be a social influence as well.”

For this reason, Liu noted that it is important to recognize that serotonin alone is only a piece of the puzzle as to why a patient may have developed depression, so treatments that solely address serotonin levels may not be sufficient for all patients.

“Therefore, we need more pharmacotherapy options,” Liu said. “When we treat patients with depression, ideally, we want to have a wide range of evidence-based options that include and expand beyond psychotherapy and antidepressants.”

REFERENCE

Liu MT. Serotonin and Beyond: Pharmacotherapy for Depression and Emerging Treatment Options. American Society of Health-System Pharmacists Pharmacy Futures 2024; June 8-12; Portland, Oregon.