Depression is characterised by affective, cognitive and somatic symptoms. The somatic symptoms are unusual in that they include symptoms of opposite polarity: increased sleep vs decreased sleep, and increased appetite or weight vs decreased appetite or weight. Around 48% of people with depression show decreases in appetite, and 35% of adults diagnosed with depression have increased appetite (Maxwell & Cole, 2009). Studies have attempted to examine subtypes of depression based on the variety of symptoms that are experienced. They have identified subtypes that showed differences mainly on the polarity of somatic symptoms (Lamers F et al., 2010; Li Y et al., 2015; Sullivan P et al., 1998).

However, it is unclear if these subtypes represent different underlying biological mechanisms, and if they therefore respond differently to treatment.

In a recent neuroimaging study, adults with depression were grouped based on changes in appetite (Simmons W et al., 2016). They found that there were differences in brain activation between adults with depression with increased versus decreased appetite. Those with decreases in appetite showed lower activation in the insula while they were looking at pictures of food. Activity in the same region in those with increases in appetite was associated with the rating of the pleasantness of the food. This is particularly interesting as the insula is involved in interoceptive processing, and integrates signals from the body, influenced by inflammatory and metabolic markers.

A relationship between inflammation and depression has been found in previous research:

• High comorbidity has been found between inflammatory conditions and depression (Bair M et al., 2003)
• People treated with immunotherapy often develop depressive symptoms (Maes M et al., 2001)
• Some studies have shown that adults with depression show higher levels of inflammatory cytokines (Haapakoski R et al., 2015).

Recently, a high association between depression and COVID-19 has been found (Steptoe A, 2020). However, the results on inflammatory dysregulation in adults with depression have been inconsistent, which might be due to the heterogeneity of depressive symptoms. A study by Simmons and colleagues aimed to address the question as to whether there are endocrine, metabolic, and immune differences between subtypes of depression (Simmons W et al., 2020).

Methods

Three groups were included in the study by Simmons and colleagues. Two of the groups consisted of adults diagnosed with Major Depressive Disorder (MDD), one group with increases in appetite (N=23) and one group with decreases in appetite (N=31). The third group is a group of healthy control subjects (N=42). In total, 96 participants were included, aged 18-47 years.

Saliva samples were collected to measure cortisol levels, and fasting blood samples were collected to measure inflammatory markers such as C-reactive protein (CRP), interleukin 1 receptor antagonist (IL-1RA) and interleukin 6 (IL-6), as well as metabolic markers such as ghrelin, leptin, insulin and glucose. Participants completed an fMRI task in which pictures of food were shown.

Results

The three groups showed differences in cortisol, metabolic and immune marker levels. These markers were also found to be associated with neuroimaging markers in the food picture task.

The increased appetite MDD group showed higher inflammation with higher levels of CRP and IL-1RA compared to the other two groups and higher IL-6 than the healthy control participants.

Metabolic markers such as insulin, insulin resistance and leptin were also higher in the increased appetite participants, whereas ghrelin was lower. Higher insulin resistance in the increased appetite MDD group was associated with higher insula activity in response to the pictures of food.

Participants with decreased appetite MDD showed higher cortisol levels. In the same group, cortisol levels were negatively correlated with activity in the ventral striatum, an area of the brain involved in reward processing.

Conclusions

The authors conclude that there are biological differences between symptom subtypes of depression. This supports the idea of biologically distinct subtypes, and suggests that changes in appetite might be a particularly useful symptom marker to discriminate between them.

The authors introduce a conceptual model in which higher cortisol leads to lower activation in the ventral striatum, which, because of the role of the ventral striatum in reward processing, could lead to decreased appetite. Increased appetite could arise by increased levels of inflammation affecting metabolic processes such as leptin insensitivity and insulin resistance. Via their effects on the insula and hypothalamus, these processes could lead to hunger and increased appetite.

Strengths and limitations

This study explores an important topic, aiming to identify homogeneous subtypes that might help us find more efficacious treatment for specific symptom subtypes. The main strength of the study is that the authors present a conceptual model of a possible relationship between increases versus decreases in appetite and distinct endocrine, metabolic and inflammatory processes. The main limitation is that the authors show only associations with the symptom subtypes, and do not show causal effects. Are these biological differences caused by the differences in symptoms or are the symptoms the consequence? A longitudinal study might help answer this.

Related to this, it remains to be determined whether the subtypes have clinical relevance. They might be expected, for example, to show different response to different treatments. This will also need to be examined in a longitudinal study design, and preferably a study that involves randomisation to different treatments.

Third, the authors only focussed on subtypes based on changes in appetite, whereas other studies have demonstrated associations between inflammation and other depressive symptoms (Lamers F et al., 2018). A subtype based on a combination of symptoms would probably show even more homogeneous underlying biological mechanisms.

Fourth, the patient groups are relatively small. It is important for the results to be replicated in a larger sample (Marek S et al., 2020). And lastly, two of the authors of the study are also co-inventors on a patent regarding appetite change in depression; a potential conflict of interest that should be born in mind.

Implications for practice

While these studies are clinically interesting, they are of uncertain significance. More studies are needed to examine the implications for treatment, as results of studies that have used anti-inflammatory medications to treat people with depression have been inconclusive.

Inflammation and depression in young people: our Active Ingredients review

The study by Simmons et al. sparked our interest as to whether young people with depression also show changes in inflammation and if these changes were associated with specific depressive symptoms.

From childhood to young adulthood the immune system undergoes significant changes. Studies have shown that during adolescence there is a decrease in immune functioning compared to childhood, which continues into adulthood (McDade T, 2003; Shames R, 2002). In addition, sex hormones cause a difference in immune function between females and males, since testosterone seems to be immunosuppressive and oestrogen at low doses is immuno-stimulatory. Therefore, we aimed to examine the association between depression and inflammation in young people as part of our active ingredients report commissioned by the Wellcome Trust.

We carried out a systematic review, reviewing all studies on inflammation and depression in young people. We included case-control studies, studies that examined associations between inflammation and depression dimensionally, longitudinal treatment studies, naturalistic prospective studies and biological induction of inflammation studies.

Based on the 97 studies reviewed, we concluded that:

• There is some evidence for subtle inflammatory dysregulation in some young people with Major Depressive Disorder (MDD). However, studies in healthy young people did not report associations between depressive symptoms and inflammation.
• In young people with MDD the differences in cytokines, inflammatory markers, were inconsistent. Most studies showed differences in the cytokines IL-2 and IFN-g, but the direction of change was again inconsistent. These cytokines were not in line with cytokines that have most consistently been found in the adult literature. There was however some evidence for a role of these cytokines, CRP, IL-6 and TNF-a, in youth depression from longitudinal studies.
• There is evidence for a bidirectional relationship between inflammation and depression from longitudinal studies, with higher inflammation being associated with subsequent depression and vice versa.
• Some factors seemed to increase the vulnerability to inflammation-associated depression such as female sex, obesity and early life stress.
• Neurovegetative symptoms, including changes in appetite and sleep, fatigue, psychomotor retardation, as well as social disconnection and anhedonia seemed to be specifically associated with inflammation.

In summary, the association between inflammatory dysregulation and depression in young people is subtle and inconsistent. This might be caused by methodological variation or the heterogeneity of depression. There might be multiple inflammatory pathways that contribute to depression, like Simmons and colleagues also proposed.

In young people there are few studies examining the effect of treatment on inflammation, but some studies in adults have shown that specific treatments might be more efficacious in reducing inflammation and reducing depressive symptoms. Since studies have shown poorer treatment response in those with inflammatory dysregulation, screening young people with depression for high levels of inflammation and/or symptom profile might help in a personalised treatment approach. However, clinical trials are needed to test if anti-inflammatory treatment or lifestyle interventions are more efficacious in young people with depression that show inflammatory dysregulation or specific symptom profiles.

Statement of interests

This work was funded by a Wellcome Trust Mental Healthy Priority Area ‘Active Ingredients’ commission awarded to Lianne Schmaal at Orygen and the University of Melbourne.

Links

Primary paper

Simmons, W. K., Burrows, K., Avery, J. A., Kerr, K. L., Taylor, A., Bodurka, J., & Drevets, W. C. (2020). Appetite changes reveal depression subgroups with distinct endocrine, metabolic, and immune states. Molecular psychiatry, 25(7), 1457-1468. https://www.nature.com/articles/s41380-018-0093-6

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