As seen in Psychology Today. Featured image from Liza Summer (used with permission).
According to the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR), there are nine key symptoms of major depressive disorder (MDD). A diagnosis requires (among other things), either depressed mood or anhedonia/diminished interest and at least five of the following symptoms throughout the same 14-day period:
1. Depressed mood
2. Anhedonia or diminished interest in most, if not all, activities
3. Severe decrease in appetite or significant weight loss (5% of body weight or more in a month)
4. Insomnia or hypersomnia
5. Psychomotor retardation or agitation
6. Fatigue or loss of energy
7. Profound sense of emptiness, guilt, or worthlessness
8. Difficulty concentrating or making decisions
9. Thoughts of death or suicide, including planning suicide
Symptoms should be experienced for the majority of the day, nearly every day, and they must represent a departure from the individual’s typical disposition.
Even if you’re not familiar with the experience of a depressive episode or the practice of diagnosing and treating them, one thing should be clear: there is a lot of variation in the symptomology. This has led to the identification of multiple subtypes of depression.
What may come as a surprise is that such variety doesn’t always translate into different treatment protocols. In other words, if a patient has met the criteria for MDD, then the clinician will often prescribe an antidepressant like sertraline (Zoloft) or bupropion (Wellbutrin), typically in conjunction with psychotherapy or another nonpharmacological treatment modality. If that doesn’t work, they may try something else. Such an approach only makes sense if the neural correlates of MDD are more or less the same for everyone. This view is being challenged more frequently as of late, and a June 2023 paper published in JAMA should be considered a wakeup call that this one-size-fits-all conceptualization of MDD is deeply flawed. The paper’s authors, a team of researchers based at Stanford University, presented evidence of a distinct subtype of MDD that could affect as many as one quarter of patients with the disorder, and this subtype is characterized by significant impairments in executive functioning, verbal memory, sustained attention, decision speed, working memory, and even psychomotor function. More importantly, this same subtype
has a far worse response to standard drug treatments, and they tend to struggle with ‘treatment resistant’ depression.
Could it be that their depression is resistant to treatment because there are distinct neural dysfunctions affecting these patients that conventional antidepressants are incapable of correcting?
According to the Stanford team, the answer is yes. They came to this conclusion after performing a secondary analysis of a previous, randomized clinical trial involving 1008 participants that was conducted between 2008 and 2013. Of these 1008 participants, 96 had subsequent brain scans. The team then used a machine learning method of cluster analysis and identified a subgroup of MDD patients who had prominent impairments in executive function and response inhibition domains of cognitive control, which translated into deficits in memory, attention, and self-control. Additionally, patients with this symptom profile showed reduced activation of the right dorsolateral prefrontal cortex, which is central to the function of the cognitive control circuit. The subgroup also had significantly greater functional impairment, more severe insomnia, and significantly greater depressive symptom severity.
“Overall, our multimodal findings suggest the presence of a cognitive biotype of depression that represents about a quarter of all depressed patients and is characterized by prominent impairments in 2 domains of cognitive control (executive function and response inhibition),” the authors wrote. Perhaps most important of all, the evidence indicates that this cognitive biotype has significantly lower remission rates compared to other patients with MDD when treated with either escitalopram (Lexapro), sertraline (Zoloft), or venlafaxine (Effexor XR).
What this all suggests is that patients with the cognitive biotype of depression will continue to struggle with depression so long as the underlying neural dysfunctions that are leading to the cognitive impairment are not addressed. This may in part explain why up to 30% of patients are not responsive to conventional antidepressants—the medications do not target the root of the dysfunction. In other words, depression is not causing patients to feel mentally sluggish or disrupting their sleep. Instead, cognitive impairment caused by neurological dysfunction in the cognitive control circuit—specifically the dorsolateral prefrontal cortex (which is key to problem solving, creative thinking, task switching, and planning) and to some extent the dorsal anterior cingulate cortex (which is central to motivation, decision-making, and emotional processing via communication with the limbic system)—is leading to symptoms of depression.
For a substantial minority of patients with MDD, perhaps as many as one in four, the first step in improving the symptoms of depression may mean improving cognition and correcting dysfunctions in the cognitive control circuit. The authors note that only one antidepressant approved by the Food and Drug Administration (FDA) has shown promise in improving cognition—vortioxetine. Unfortunately, it is not clear through what mechanism of action makes vortioxetine improve cognition. Of note this is a single study and does not suggest that only one medicine (Vortioxetine) is to be used; further analyses with other treatments are warranted.
As much as we may want a cure for depression, this research is a reminder that MDD is not an acute problem. It is not like an infection that can be remedied with a course of antibiotics. Rather, there are numerous etiologies and biotypes of MDD, and clinicians need better diagnostic tools to recognize them.
The more granular our knowledge of these biotypes and their neural correlates becomes, the better we will be able to develop treatments that target the underlying dysfunctions causing the disorder. As these treatments become more precise, it will ultimately help us alleviate patients’ symptoms and give them the opportunity to live a life without depression.
This article was written entirely by a human with no assistance from generative AI tools.