The Neurobiological Basis of Major Depressive Disorder (MDD)

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Major depressive disorder (MDD) which is also known as either unipolar depression or major depression is a common yet disabling mental disorder affecting over 400 million people worldwide with a higher incidence in women than men (World Health Organisation, 2012). Depression may be endogenous where there is no discernible cause or reactive whereby the depression is a result of an incidence such as the loss of a parent, loved one or stress. Some of the emotions that individuals may experience with depression are, feelings of sadness, anger, bitterness and resentment, emotions which can last a few days or in some cases, months and have a huge impact on the individuals life. Some individuals suffering from MDD are also more likely to have a substance abuse problem, other mental and physical problems, and are likely to have a greater suicide risk. MDD is a widely researched topic with a sense of urgency to find the exact aetiology and pathophysiology behind the disease so that a more thorough understanding can be reached and treatment can be uniquely designed for each individual. Researches surmise that various factors are involved such as the chemical changes in the brain, genetic predispositions and environmental factors. The aim of this essay, although not comprehensive enough, is to try and bring together research material from various sources and highlight some key areas around MDD such as a synopsis of the aetiology, pathophysiology, risk factors, treatments and test available today.


The underlying aetiology (causes) of MDD is so complex with many gaps that it appears that no-one is quite sure what causes depression, however much research done to date into this condition suggests that a combination of factors are involved, such as genetics, an individual’s biochemical environment, personal experiences and psychological factors. According to Dr Michael Miller, a Professor of Psychiatry at Harvard University (2013), several forces interact to bring on depression including faulty mood regulation by the brain, medications, medical problems, genetic vulnerability and stress. In as much as age related brain changes, disease related changes , for example, cerebrovascular disease, Parkinson’s disease, and epilepsy, lead to disruptions in the circuitry of emotion regulation and can cause the onset of depression (Wryobeck, Haines, Wynkoop and Swanson, 2013). Areas of the brain underpinned by major depressive disorders such as the thalamus, the hippocampus and the amygdala (Limbic circuitry) (Figure 1. Miller, 2013 ) include several groups of neurons and white matter. Cell connections, nerve cell growth, and the functioning of nerve circuits in the brain have a major impact on how the brain functions, particularly in the way they communicate with each other. Several different chemicals and hormones working within and outside these nerve cells play a key role, with reduced levels of serotonin and noradrenaline posit to be a huge factor associated with the disease (Miller, 2013). Similarly, Villanueva (2013) through the construct of a survey used to assess the neurobiology of MDD, found that brain-derived neurotrophic factor (BDFN) along with expressions of miRNA’s (involved in neural plasticity), abnormal gastrointestinal signalling peptides and proinflammatory cytokines are all causative factors of major depressive disorder. What proinflammatory cytokines do, is stimulate the hypothalamic-pituitary-adrenal axis, activate secretion of growth hormone and inhibits the thyroid stimulating hormone secretion, all of which are associated with depression. Whereas gut microbiota (flora), specifically leptin, ghrelin and cholecystokinin (signalling peptides), influence the central nervous system including modulation of neurogenesis which can influence brain chemistry and consequently an individual’s behaviour.

According to Lopresti, Hood and Drummond (2013), as seen in figure 2 below, a bi-directional relationship is likely to exist between depression and lifestyle factors with key symptoms including changes in appetite, general energy levels, motivation levels and sleep, which in turn affect diet, exercise and sleep thereby creating a cycle of influence. A vicious cycle, all of which point to the necessity of promoting lifestyle changes

Figure 2. Potential mechanism of diet, sleep and exercise on major depression. In Lopresti et al. (2013).

Another avenue suggested by Dr Miller (2013), is that research has identified that genetics play a role, in that not only do certain genes make individuals more vulnerable to low moods, but it can influence how individuals respond to drug therapy. Likewise, Stanford school of medicine surmise that through its research on the study of identical (100% genetically identical) and non-identical twins (50% genetically identical) and major depression as a heritability factor, heritability shows to be a huge contributor in the development of this disease. Each individual inheriting a unique combination of genes, with a predisposition to certain illnesses (Levinson and Nichols, n.d.). Genes controlling either the production or utilization of serotonin plays and important role in the pathogenesis of depression and in particular with serotonin reuptake due to the fact that depressed individuals have a lower rate of serotonin uptake. In depression of the elderly or late onset depression, genetics is less common or does not appear to play a role as genetic markers are not present (Halverson, Bhalla, Bhalla and Andrew (2014). In so saying then, non-genetic factors, many of which are not known, also need to be taken into account, as Levinson and Nichols (n.d) suggest, these factors also increase the risk and progression of depression.


Progression of the illness as indicated by Treadway et al.(2014), is linked to biological changes. Due to over-stimulation of steroidal and inflammatory signalling molecules by stress, structural abnormalities within the prefrontal cortex and hippocampus, known for regulating behaviour and endocrine responses to stress, can be damaged. Moreover diet, sleep and exercise not only play a significant role in the development and progression of the illness, it also impacts on the treatment. One research analysis undertaken by Maletic, Robinson, Oakes, Lyengar, Ball and Russell (2001), summarised that MDD involved structural, functional and molecular alterations within the brain. Similarly research conducted by Halverson et al. (2014), speculates that although the underlying pathophysiology of MDD has not been clearly defined, studies show a strong interaction between the neurotransmitter availability and receptor regulation, with emphasis again on serotonin activity disturbances in the central nervous system. Other neurotransmitters such as epinephrine, dopamine, glutamate and brain derived neurotrophic factor (BDNF) are also implicated in depression. Cells within the hypothalamus are responsible for an individual’s emotional state which in turn link to the stress responses. Several studies , in particular Lopresti et al. (2013), show that during stressful times, the hypothalamic – pituitary-adrenal axis (HPA), the neuroendocrine circuit that manages stress in the body, becomes activated. This then leads to the release of epinephrine and glucocorticoids (cortisol) to assist the body in its adaptive response to stress. However, if the body remains under a constant state of stress, excitotoxicity of neurons, particularly in the hippocampus can occur leading to dendrite atrophy and apoptosis of neurons (Wryobeck et al. 2013). Research shows that while cortisol helps the brain to cope with stressful situations, it also damages and kills cells in the hippocampus. So it can almost be said that stress excites brain cells to death. Furthermore research shows that individuals experiencing depressive disorders have a smaller hippocampal volume than individuals who do not from depression and that positron emission tomographic (PET) showed a diminished activity in the area of the prefrontal cortex in individuals with depressive disorders. Thereby underlying the functional and structural abnormalities in the brain regions of individuals suffering from depression (Halverson et al. 2014). Most individuals with MDD present with normal appearance however, individuals with more severe symptoms may present with more significant signs such as, poor hygiene, poor grooming and changes in weight. Individuals with MDD have a distorted view of their life whereby negative attitudes make it more difficult to see a positive outcome from a difficult situation. Other symptoms such as psychomotor retardation, agitation or restlessness, suicidal thoughts or attempts, social withdrawal and in the elderly somatic complaints may also be evident. These however are only some of the underlying signs and symptoms as individuals vary from one to the next.

Risk factors / causal agents

It is a widely held view that there is an unambiguous relationship between physical, psychological, environmental, genetic and social factors as well as a dysregulated response to chronic stress as risk factors for depression. Halverson et al. (2014) infer that stress plays a dominant role in depression due to the chemicals involved throughout the body such as adrenaline and cortisol which in abundance, leads to other health complications. With the various types of onset of stress being for example, the loss of a parent prior to the age of 10 years, parent-child relationships, due to poor interaction between the two and child stressors, which can contribute to depression or thought to be associated with both early and late abuse and neglect. In addition, stressful changes in life patterns such as a serious loss, difficult relationships, trauma or financial problems can trigger a depressive episode. Women with a previous history of depression are at higher risk of menopausal depression while low testosterone levels in older men also aid in onset of depression (Halverson et al. 2014). Likewise Martin (2014) highlights that women may experience more episodes of depression than men due to hormonal changes such as during premenstrual phases, pregnancy, postpartum and menopause. Coupled with this is the additional stress of work-life balance where women take on the added responsibility of tending to children and or aging parents whilst still trying to forge a career for themselves. Individuals with a family history of depression tend to be at higher risk of developing depressive disorders.

Psychosocial risk factors according to Halverson et al. (2014) can include impaired social supports, caregiver burden, loneliness, bereavement and negative life events. Abused substances and pharmacological agents can increase depression risks due to altering brain chemicals. These include pain relievers, sedatives, sleeping pills, cortisone drugs and seizure drugs, to name but a few. Whilst in the elderly, neurodegenerative diseases particularly Alzheimer’s and Parkinson’s, stroke, macular degeneration (vision) and chronic pain can all contribute to higher rates of depression (Martin, 2014).

Treatment strategies

First and foremost, education plays an important role in the treatment of MDD as individuals may become aware of the signs of relapse thereby allowing them to seek early treatment. Family and support members also need to be educated about the nature of depression and the treatment involved so as to be able to give the support needed, ensure medication compliance and encourage a change in lifestyle such as keeping active (Halverson et al. 2014). Wryobeck et al. (2013), posit that with depression being a multi-factored illness, treatment should encompass a combination of therapies such as psychotherapy, electroconvulsive therapy, lifestyle management, psychosocial therapy and pharmacotherapy.

Pharmacotherapy such as anti-depressants being one method affects the neurotransmitters. Selective serotonin re-uptake inhibitors (SSRIs), a new class of antidepressants, which allow for the increase of serotonin by blocking the re-uptake of serotonin into the presynaptic neuron, is according to Clarke and Gordon (2011), used as the first line of treatment. SSRIs allow for autoreceptors to be desensitised or down-regulated, nerve transmission and serotonin levels are normalised and mood is elevated. Figure 3 below, illustrates how the amount of neurotransmitters in individuals with depression are reduced and postsynaptic receptors are increased as a response to these lower levels. The re-uptake of serotonin adding to the decreased amount of neurotransmitters. When treatment of SSRIs take place, serotonin levels increase due to the blocking of the re-uptake and down-regulation of postsynaptic receptors occur (Clarke & Gordon, 2011).

Figure 3 Action of selective serotonin re-uptake inhibitor drug. In neurobiology of mental illness Clarke & Gordon (2011).

Psychotherapy can include behaviour therapy, cognitive-behaviour therapy, family therapy, interpersonal therapy, psychodynamic psychotherapy and supportive psychotherapy. Psychosocial therapies according to Halverson et al. (2014) and supported by The American Psychiatric Association (APA) is often a first-line of treatment for mild cases of depression however, in more severe cases this should be combined with antidepressant medication.

Other approaches according to Wryobeck et al. (2014) and Halverson et al. (2014), can include electroconvulsive therapy (ECT) which is thought to increase neurogenesis, reversing degeneration and decreased proliferation of nerve cells, regulate neurotransmitters and correct dysregulation of neuropeptides. Stimulation techniques such as vagus nerve stimulation which involves the nerve to be stimulated with electrodes resulting in the assumption that it may alter norepinephrine release and elevating levels of inhibitory GABA. Transcranial magnetic stimulation concentrates magnetic energy over parts of the brain allowing for either an increase or decrease in cortical excitability depending on the frequency. Stimulation over the right frontal lobe apparently reduces the symptoms of depression. Talk therapy as well as exercise are more non-invasive forms for dealing with MDD allowing the individual to develop problem solving skills, coping mechanisms and in some instances to form a support group.

Relevant tests

To date there are no physical findings that are specific to MDD, instead diagnosis is dependent on the individual’s history and mental state exam. As depression may be linked to an underlying physical problem, both a physical exam as well as thyroid function blood tests can be done. A psychological evaluation is also of benefit to gather information around an individual’s feelings and behaviour pattern. In New Zealand a wide range of tools are available such as the Kessler 10 (K10) for assessing depression, anxiety and general mental health, the patient health questionnaire (PHQ-9) for depression and the GAD-7 for anxiety assessment. According to the Best Practice Advocacy of New Zealand [bpac z](2009) these tools also allow for monitoring the response to an individual’s treatment regime to ensure that optimal health is being met.

In conclusion, to date the specific causes of major depressive disorders (MDD) is still unknown, however a substantial amount of research has gone into and still continues in this area with a consensus that depression appears to be a multifactorial and diverse group of disorders involving the chemical reactions and nerve communication in the limbic circuitry of the brain and both genetic and environmental factors. Progression of MDD is linked to biological changes, diet, sleep and exercise. Treatment strategies appear to be multi-factored with underlying assumptions based on individual research results. Education is still an important element focusing on the individual and support structures while more up to date pharmacopeia such as serotonin re-uptake inhibitors, lead the market as the go to drug for antidepressants. Most literature to date however, underlines the need for more research to take place, in particular, within the area of the aetiology / pathophysiology of the disease and likewise specifically structured individual treatment strategies.


Clarke, G. & Gordon, C. (2011). Neurobiology of mental illness. In J. Craft, C. Gordon & A. Tiziani (Eds.), Understanding pathophysiology (pp. 1177-1180). Chatswood, NSW: Elsevier.

Halverson, J. L., Bhalla, R. N., Bhalla, P. M. & Andrew, L. B. (2014). Depression. Retrieved from

Levinson, D.F. & Nichols, W.E. (n.d.). Major depression and genetics. Retrieved from

Lopresti, A. L., Hood, S. D. & Drummond, P. D. (2013). A review of lifestyle factors that contribute to important pathways associated with major depression: Diet, sleep and exercise. Journal of Affective Disorders 148 (2013), 12-27.

Maletic, V., Robinson, M., Oakes, T., Lyengar, S., Ball, S. G. & Russell, J. (2007). Neurobiology of depression: an integrated view of key findings. International journal of Clinical practice, 61 (12), 2030 – 2040. doi: 10.1111/j.1742-1241

Martin, B. (2014). What are the risk factors for depression? Retrieved from

Miller, C. M. (2013). What causes depression. Retrieved from

The Best Practice Advocacy centre of New Zealand. Assessment of depression in adults in primary care. (2009). Retrieved from

The world health organisation. (2012). Depression fact sheet. Retrieved from

Treadway, T. M., Waskom, M. L., Dillon, D. G., Holmes, A. J., Park, M. M., Charavarty, M. M., ‘…’, Pizzagalli, D. A. (2014). Illness progression, recent stress and morphometry of hippocampal subfields and medial prefrontal cortex in major depression. Society of Biological Psychiatry. Retrieved from

Villanueva, R. (2013). Neurobiology of major depressive disorder. Neural Plasticity, volume 2013. doi: 10.1155/2013/873278

Wryobeck, J. M., Haines, M. E., Wynkoop, T. F. & Swanson, M. M. (2013). Depressive disorders. In C. Noggle & S. Dean (Eds.). The Neuropsychology of psychopathology (pp 201-220). New York, NY: Springer Publishing.

List of illustrations

Figure 1. Miller, C. M. (2013). What causes depression. Retrieved from

Figure 2. Lopresti, A. L., Hood, S. D. & Drummond, P. D. (2013). A review of lifestyle factors that contribute to important pathways associated with major depression: Diet, sleep and exercise. Journal of Affective Disorders 148 (2013), 12-27.

Figure 3. Clarke, G. & Gordon, C. (2011). Neurobiology of mental illness. In J. Craft, C. Gordon & A. Tiziani (Eds.), Understanding pathophysiology (pp. 1177-1180). Chatswood, NSW: Elsevier.

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