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  • Writer's pictureMilena Georgieva

A guide on how to deal with chronic depression: when psychotherapy and pharmacotherapy don't work.

Updated: Apr 3, 2023

Part 1. Understanding depression.

This article will be part of a series of articles exploring the causes and management strategies for chronic depression. I will attempt to provide an overview of the potential driving mechanisms of depression, their evidence base, and some suggestions for management strategies. The topic is quite extensive, so I have broken it down into chunks.

The content provided will be based either on information published in scientific journals and books or what I have found to be helpful through my experience dealing with chronic depression in a professional or personal capacity.

The purpose of this series is to hopefully provide a somewhat systematic framework to create a better understanding of and a management plan for chronic depression - or at least be a starting point of inquiry.

Series overview:

Part I will explore the standard view of depression and chronic depression, along with the standard recommended treatments, and introduce the proposed alternative functional medicine approach to treating chronic depression.

Part II and beyond will be exploring the factors implicated in the aetiology (cause) and maintenance of depression: what they are, what the evidence is for their involvement in depression, and how to manage them.

Part II and beyond: Creating a management plan for depression.

  • Stress, the HPA axis & inflammation (Part II and Part III)

  • Gut health (Part IV)

  • Loneliness and social isolation (Part V)

  • Trauma and adversity (Part VI)

  • Vitamin deficiencies and other underlying pathophysiology: hypothyroidism & adrenal insufficiency (Part VII)

Disclaimer: I am not a medical professional and this is not medical advice.

What is depression: symptoms and types of depression

Let’s start with the basics: depression is a mental health disorder - a standard medical definition of a disorder is “a disturbance of normal functioning of the mind or body” (National Cancer Institute, n.d.). We also know that not all depression looks the same - there are different types of depression. This is recognised by The Diagnostics and Statistical Manual of Mental Disorders 5th Edition (DSM 5) - which is one of the two big diagnostic manuals used by clinicians in healthcare and mental health settings to understand, recognise and inform treatment of mental health conditions (the International Classification of Diseases 10th edition being the other one).

The DSM 5 recognises depressive disorders as an umbrella term that describes disorders featuring “sad, empty, or irritable mood, accompanied by somatic and cognitive changes that signifi­cantly affect the individual's capacity to function.” (American Psychological Association, 2013, p. 155).

Depressive disorders umbrella term DSM 5

The most well known depressive disorder is probably Major Depressive Disorder (MDD) - it is the “classic” condition, that involves “discrete episodes of at least 2 weeks’ duration, involving clear-cut changes in affect, cognition, and neurovegetative functions and inter-episode remissions”, (American Psychological Association, 2013, p. 155) with the high likelihood of relapse in most cases. Key features are (1) significantly depressed mood, (2) markedly diminished interest or pleasure, (3) significant changes in weight or appetite, (4) significant changes in sleep (insomnia or hypersomnia), (5) psychomotor agitation or retardation observable by others, (6) fatigue, (7) feeling worthlessness or excessive guilt, (8) diminished ability to think or concentrate, (9) recurrent thoughts of death & suicidal ideation. (American Psychological Association, 2013, p. 161).

A lesser known depressive disorder also recognised by the DSM 5, but perhaps even more insidious to treat, is Persistent Depressive Disorder, also known as chronic depression. It is marked by episodes that persist for longer than 2 years and it shares most of the same features of MDD apart from two (markedly diminished interest or pleasure and thoughts of death & suicidal ideation).

Chronic Depression Symptoms

It’s important to note that chronic depression is different from an acute depressive episode - whilst both share many of the same symptoms, chronic depression is long-term and tends to be less severe in intensity (although exceptions occur).

Lastly, we know that depression is somewhat common. The estimated prevalence of major depressive disorder in Europe is relatively high at 6.38%, with significant variation across countries (ranging from 2.58% in the Czech Republic to 10.33% in Iceland) (Arias de la Torre et al., 2021).

Depression standard treatment guidelines

The DSM 5 states that it “is intended to serve as a practical, functional, and flexible guide for organising information that can aid in the accurate diagnosis and treatment of mental disorders.” (American Psychological Association, 2013, p. xli). The DSM 5 is a useful tool as a diagnostic manual, but it holds no information on treatment approaches, strategies or recommendations. For that, we would have to turn to institutions, such as the National Institute for Health and Care Excellence (NICE)** (In the US, the organisation that sets the treatment standard is the American Psychological Association). Amongst other tasks, NICE develops guidance on the appropriate treatment and care for people with certain conditions and diseases, which is used by the NHS and private clinics and clinicians.

**NICE is an executive non-departmental public UK body, sponsored by the Department of Health and Social Care (Government Digital Service, n.d.).

If we go to the NICE’s website for treatment guidance (National Institute for Health and Care Excellence, 2022) their recommendations for first episodes of mild and severe depression are individual or group psychotherapy, medication, and self-help. For chronic depression the choices are limited only to medication and social support for those struggling with significant social withdrawal, perhaps reflecting the perceived diminishing utility of continual therapeutic care if the patient was a non-respondent in the first place.

Treatment options for chronic depression UK

Generally speaking, when someone accesses the NHS to get help with depression, they currently have two choices - antidepressant medication or psychotherapy, also called talking therapies (National Health Service England, 2022). If the person goes to their GP, they can be offered antidepressant medication, with sertraline and fluoxetine (prozac) being the first choice. Therapy at a local talking therapy service can be accessed either through their GP or through a direct self-referral. The local talking therapies service provides psychotherapy to those struggling with depression (there are long waiting lists for it and patients can only access a limited number of sessions, but these issues are beyond the scope of this article). Once a patient has had all their sessions, they are discharged and they can get referred to the service again.

How well do psychotherapy and medication work?

What we know about remission rates for antidepressants is that they are around 50% to 60% compared to 30% for placebo (Dawson et al., 2004), depending on which study you look at. The statistics are similar for psychotherapy. The remission rates for psychotherapy combined with medication fare slightly better at 67% perhaps due to the small sample size (Dawson et al., 2004). This still means that about a third of all depressed people do not respond to the standard treatment protocols - potentially leaving them chronically depressed.

Effectiveness of therapy and medication depression
Note: Psychotx = Psychotherapy, Antidepr = Antidepressants, pts = patients. Source:

Now this brings one glaring question: what do we do with those for whom therapy and medication are only helping a little bit, if at all? What is a good way to treat or manage chronic depression?

How should we treat chronic depression when someone doesn’t respond to the standard treatment? Functional medicine approach vs the standard medicine approach.

To figure out how to treat chronic depression, we need to go beyond the symptoms, and think about what causes it. Currently what we have from the DSM 5 is a label that describes the symptoms, which does not tell us about aetiology or driving mechanisms. NICE has a set of treatment guidelines, which are limited to talking therapies and antidepressant medication. However, neither of these tells us anything about what is driving these symptoms or how to tackle them in a comprehensive way.

The truth is that chronic depression is multicausal. In other words, there are a multitude of factors that are driving and maintaining these symptoms. In recent published scientific literature, it has been established that psychosocial stressors (trauma, adverse events & loneliness), physiological changes (gut, autoimmunity & inflammatory processes), and lifestyle factors (nutrition, sleep quality, exercise) all contribute to the development and maintenance of depression (Maletic & Raison, 2017). In scientific terms, this is called causal heterogeneity (Maung, 2016) and the implications for treatment is the use of a functional medicine approach (The Institute for Functional Medicine, 2022).

On the other hand, what we have now with respect to depression treatment does not reflect this multicausality. The current treatment reflects the standard medical model: one disease with one cause - the so called serotonin hypothesis. Without going into too much detail, the current prevailing explanation for depression in medical practice is that it’s linked to changes in brain neurochemicals, most notably serotonin, but also dopamine and norepinephrine. The explanation goes that these brain changes occur because of inherent biological differences or due to adverse events like trauma or chronic stress. To fix the brain’s neurochemistry (the cause), one can give people medication which will alter their neurochemistry directly, or put people into therapy, which will alter their neurochemistry indirectly through changing their behaviour, thoughts, etc.

But research shows that this hypothesis is flawed because it misses out on potentially more important driving mechanisms like chronic stress and immune activation (Maletic & Raison, 2017). We base our treatments around the serotonin hypothesis and the majority of the public (85-90%) believes it (Pilkington, Reavley & Jorm, 2013, as cited in Moncrieff et al., 2022). Meanwhile, this hypothesis has recently been questioned as evidence mounts that it is inadequate (Moncrieff et al., 2022). The standard one disease one cause view has most likely stuck around because it is the status quo in medicine and because there is a significant time lag between research and its translation into medical practice - and this translational lag is a well established phenomenon in medicine (see for example Morris et al., 2011)

Functional medicine approach to depression

Treating chronic depression with a functional approach - a mindset shift

The issue here is that by fixating on a specific cause (the neurochemistry of the brain), and failing to acknowledge the causal heterogeneity of depression, we are missing out on important therapeutic mechanisms that are not tied into serotonin or other receptors. Therefore, we are missing out on a multitude of possible interventions, such as activity scheduling, exercise, nutritional support, light therapy, etc.

There are challenges in using a functional medicine approach for the treatment of depression. Firstly, it means tailoring the interventions to the specific case - figuring out what contributes to someone’s depression can be somewhat complicated. Secondly, this approach might be difficult to upscale and implement in a socialised healthcare system to roll out for everyone. Lastly, it requires knowledge from a multitude of disciplines (from human behaviour and psychology to nutrition and immunology), which would require a team of specialists and/or access to various resources.

On the bright side, there are also many opportunities. Firstly, it opens up doors to people who have only minimally responded to psychotherapy and medication. Secondly, it means that there is a wider range of tools to select from to create treatment and management plans - with the possibility of combining different interventions to increase remission rates. Lastly, it also means that relatively inexpensive and easy to implement interventions like exercise plans could boost remission rates at the fraction of the cost.

The bottom line:

  • Chronic depression is caused by a multitude of factors - psychological in their nature, such as trauma, adverse life events, loneliness & stress, and physiological in nature, such as inflammation, gut health, ill health & brain neurochemistry.

  • This means that the treatment for chronic depression, particularly where simple therapy and medication hasn’t worked, should address a multitude of these contributing factors.

  • This opens up opportunities to offer more than just therapy or medication and - instead to offer a range of psychological and physiological interventions and combine them appropriately (psychotherapy, behavioural activation, exercise, diet modification, supplementation, medication, etc.).

  • This would allow people with chronic depression to create a management plan including lifestyle, dietary, social etc. changes, potentially supplemented with therapy and/or medication, that allows them to live a life free of depression.

Interesting fact:

It is likely that depression is a condition in which the human organism adapts to environmental adversity - psychosocial, physiological and infectious stress. The common theme between all the factors that can cause depression is that they pose a threat to an organism’s evolutionary fitness. Some of the hallmark signs of depression are either a consequence of the adaptation or are the adaptation itself. For example, in response to social isolation, the body mounts an immune response and produces inflammatory molecules. These inflammatory molecules, called cytokines, cause people to engage in “sickness behaviour” - in other words, to withdraw socially and behaviourally, and to experience anhedonia. This is an adaptation - or a response - to environmental adversity. In this case the environmental adversity trigger is a psychosocial stressor in the form of social isolation, but the trigger could also be a traumatic event, chronic stress, inflammation from diet and so forth (see Maletic & Raison’s book for more in-depth research and explanation of this theory and all the evidence-based factors that contribute to the development of depression).


Government Digital Service. (n.d.). National Institute for Health and Care Excellence. GOV.UK. Retrieved March 29, 2023, from

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).

Arias de la Torre, J., Ronaldson, A., Vilagut, G., Peters, M., Valderas, J. M., Serrano-Blanco, A., Martín, V., Dregan, A., & Alonso, J. (2021). Prevalence of major depressive episode in 27 European countries. European Journal of Public Health, 31(Supplement_3).

Dawson, M. Y., Michalak, E. E., Waraich, P., Anderson, J. E., & Lam, R. W. (2004). Is remission of depressive symptoms in primary care a realistic goal? A meta-analysis. BMC Family Practice, 5(1).

The Institute for Functional Medicine. (2022, October 3). What is functional medicine?: IFM. Retrieved March 29, 2023, from

Maletic, V. and Raison, C. (2017). The new mind-body science of depression. W. W. Norton & Company

Maung, H. H. (2016). Diagnosis and causal explanation in psychiatry. Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences, 60, 15–24.

Moncrieff, J., Cooper, R. E., Stockmann, T., Amendola, S., Hengartner, M. P., & Horowitz, M. A. (2022). The serotonin theory of depression: A Systematic Umbrella Review of the evidence. Molecular Psychiatry.

Morris, Z. S., Wooding, S., & Grant, J. (2011). The answer is 17 years, what is the question: Understanding time lags in translational research. Journal of the Royal Society of Medicine, 104(12), 510–520.

National Cancer Institute. (n.d.). NCI Dictionary of Cancer terms. National Cancer Institute. Retrieved March 29, 2023, from

National Health Service England. (2022). NHS talking therapies. Retrieved March 29, 2023, from

National Institute for Health and Care Excellence. (2022). Overview: Depression in adults: Treatment and management: Guidance. Retrieved March 29, 2023, from

Pilkington, P., Reavley, N., & Jorm, A. (2013). The Australian public's beliefs about the causes of depression: associated factors and changes over 16 years. Journal of Affective Disorders,150(2). doi: 10.1016/j.jad.2013.04.019.

1 Comment

Mar 30, 2023

Wow, it really is shocking how basically everything that current treatment methods are based on has left this whole multitude of factors for causes of depression (and the multicausality) out of consideration. I think this should be discussed more.

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