Short introduction

I'm studying depression from a biochemical point of view. My interest lies in the study of protein biomarkers and I was wondering which cell lines may be appropriate for this purpose. It is not important that the biomarkers occur in easily accessible tissue or matrices, as this is not the exploration of a new diagnostic method. Rather, it is important to obtain the most accurate information possible about protein expression in the neuronal environment, where depression is supposed to occur.

In my literature research, I came across two quite commonly used cell lines, both of which have their advantages and disadvantages. Let's have a look at them:

LCL cells

LCL cells are produced by infecting lymphocytes with the Epstein-Barr virus.


  • They are relatively easy to have produced individually, so it is perfectly possible to get cell lines from patients with a diagnosed depression and from patients that are very unlikely to be depressed.
  • They were already used for studying depression-related topics [1, 2]


  • LCL cells are not neuronal cells, which means that they might (and probably will) express a different set of proteins than neuronal cells.

SH-SY5Y cells

SH-SY5Y cells were subcloned from a cell line that was isolated from a bone marrow biopsy taken from a four-year-old female with neuroblastoma. The subclones were chosen such that individual cells with neuron-like characteristics were selected.


  • One could argue that SH-SY5Y cells are pseudo-neuronal cells, which is why they are commonly used to study neuronal diseases such as Parkinson's disease and other neurodegenerative diseases. [3, 4]


  • The cell line is not personalized, i.e., it's impossible to get cells from depressed and non-depressed patients, thus it's tricky to find biomarkers for depression, if you cannot compare a "healthy" with an "unhealthy" protein expression.


Do you know any readily available cell line that could be used to find differentially expressed proteins in depressed subjects that is close to neuronal cells? Neuronal cells from the cerebrospinal fluid (CSF-contacting neurons) would probably be the best one could get from living subjects, but the setup of an approveable study and the recruitment of subjects that voluntarily accept a lumbar puncture is a bit tricky to say the least.


1 Answer 1


tl;dr there is no 'depression' cell line. Cell lines would be suited for studying pharmacology, cellular or molecular mechanisms, none of which are depression. Depression also has no good correlates on the molecular level which can be used as a proxy by virtue of using in vitro cell lines. For instance, you can use cell lines to study amyloid protein biosynthesis or clearance to better understand the proteostasis that occurs in neurodegenerative disease, which are thought to arise through aberrant proteostasis. But depression itself is poorly defined and is less characteristic than that on a molecular level, and I certainly don't know of any cell lines that can be used to study "differential expression of genes in depressed folks". You'd be better prepared by taking brain biopsies and even that would be very incomplete of a picture to begin a study.

Hi Sam. Really interesting idea, you certainly pose the question diligently. Do not be discouraged from thinking about such things following a read through my response. But... I think many first impressions here would include critical thoughts about how you formulate and think about the experiment.

Thus, I would challenge your question. First, depression is a syndrome, and is not very clearly defined, certainly not well at the molecular level. If you want to reduce depression to a mechanism study-able in cell lines, you first need to justifiably operationalize it somehow. This I think is very problematic already.

Additionally, depression does not occur at all in cell lines, or even between neurons in synapses, but rather (loosely speaking...) in vast, interconnected circuits, as its readout - symptomatology - are observable only as the output of entire nervous systems, in organisms. Depression is not caused by faulty enzymes as results of single mutations; they are very highly multi-faceted. As such, cell lines cannot be used as proxies. What cell lines can be used for is to study specific molecular interactions, say with how pharamaceuticals are metabolized, or which compounds may impact proliferation. However, here I quote a few things from one of your sources that jump out even during a quick skim read:

On the basis of the neurotrophic hypothesis of antidepressant’s action, effects of antidepressant drugs on proliferation may serve as tentative individual markers for treatment efficacy

Peripheral proliferation is unsuitable as surrogate marker for antidepressant response

Although the in vitro treatment of patient-derived LCLs with fluoxetine presents high inter-individual variability regarding the LCL proliferation behavior, this phenomenon has—according to our data—no association with the patient’s clinical outcome.

The paper merely screened for differential expression in genes in white blood cells following fluoxetine exposure, and found only two candidate genes, SULT4A1 and WNT2B, which they have some reason to believe may be involved in drug metabolism, which were correlated to a donor clinical response and remission, respectively. This is a paper which suggests potential candidates for further study, but does not at all implicate or demonstrate any connection at all between depression or the efficacy of the drug, or the genes involved. It is meager in lieu of your question! The key here is that they compare cells before and after fluoxetine exposure, not that they are comparing depressed or non-depressed neural tissue. They tried to use remission to correlate things, but it just didn't work well. Which I think is expected!

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    $\begingroup$ Thank you for this very detailed answer. Reading your take on this gives the impression that you don't think that it's even possible to study depression in cell lines. This may be true if you want to correlate your findings with a clinical outcome but it's certainly not true if you're interested on the cellular level only. It's clear that depression is a very complex syndrome and I think that it's also safe to say that many factors play an important role here, but nevertheless there are multiple studies showing that subjects with a diagnosed MDD do show differentially expressed proteins. (1) $\endgroup$
    – Sam
    Aug 5, 2021 at 13:24
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    $\begingroup$ A polymorphism within the promoter region of the serotonin transporter gene (SERTPR) was thought to be a risk factor for the development of depression (Mandelli et al 2007). Significant associations have been described between single nucleotide polymorphisms in the FKBP5 gene and antidepressant response and recurrence of depressive episodes (Binder et al 2004). A polymorphism in the GNB3 gene was also found significantly more often in depressed than in healthy controls (Zill et al 2000). This shows that it's safe to say that there are proteomic differences in depressed subjects. (2) $\endgroup$
    – Sam
    Aug 5, 2021 at 13:33
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    $\begingroup$ We want to take this further by determining potential biomarkers for depression by bottom-up LC-MS analysis from neuronal cells to subsequently identify possible long-term risk factors, for example, long-term use of specific drugs. For this purpose, cells are needed that can be incubated with the drugs. (3) $\endgroup$
    – Sam
    Aug 5, 2021 at 13:38
  • $\begingroup$ As a counter-example to your opening sentence, see Lithium-responsive genes and gene networks in bipolar disorder patient-derived lymphoblastoid cell lines, published in Nature in 2016 (Lithium has been used as a very effective drug in the management of manic depression since the 1960s) $\endgroup$
    – user338907
    Aug 5, 2021 at 17:31
  • $\begingroup$ @Sam You can look for biomarkers in a cell line but how do you know they have anything to do with depression? Your cells won't be depressed. You can certainly study a gene of interest in a cell line, but still that cell line won't be depressed. The cell type you use probably doesn't matter much - HEK cells, primary neurons, whatever you want, they won't be depressed either, they will just express your allele of interest. $\endgroup$
    – Bryan Krause
    Aug 5, 2021 at 17:32

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