Understanding Depression: Causes, Pathophysiology & Therapy Explained

what is depression

What is depression? This question is something that has remained unanswered since ages. Individuals suffering from depression want to know ‘what is depression’ in the sense that how it affects their body.

Loved ones of depressed individuals try to ascertain the answer to this question in the sense of understanding how it could be treated.

Scientists attempt to describe or define depression on biochemical and molecular grounds.

Most resources describe depression as a serious mood disorder, more than just a low mood, which lasts for long periods of time and affects one’s day to day life. That is a pretty close definition for most individuals diagnosed with it and whose symptoms and diagnosis have been reported.

However, this definition is not applicable to all. We are unique in every sense and since this is a disorder that affects our cognition as well as emotions it is important to understand that every individual facing depression presents with different symptoms and may have different trigger factors for the same.

This article attempts to cover a general overview of what exactly is depression as a disorder, possible causative factors, common symptoms and possible treatment options.

What Is Depression?

Depression is one of the ailments coming under the category of ‘Mental illness.’ Depression comes from the Latin word depressare and the classical Latin word deprimere which means “press down.”

This denotes a sense of heaviness, or suppressed feelings or simply feeling ‘down.’

It can affect any age group from childhood to late life. It primarily affects an individual’s emotional and thinking process and involves a number of symptoms, but three major or common emotional symptoms include:

  • Low mood
  • Anhedonia or lack of interest
  • Fatigue or lack of energy

Researchers acknowledge that it is not a ‘homogeneous disorder but complex phenomenon’ and has different types each of which may have different manifestations. It may have episodic or progressive periods of mood disturbances.

It can present with severe symptoms such as psychosis and may also integrate with somatic changes or physical symptoms. Mostly a high incidence of anxiety and panic disorder is observed with depression.

It affects the gastrointestinal (stomach or digestive system) system, immunity and even cause hormonal imbalance.

Sleep disturbances, change in appetite, feelings of guilt, lack of self-worth or self-confidence, reduced ability to take decisions, grief, lack of clear thinking or disturbed cognition are few commonly observed signs of depression.

Higher incidence of depression is observed in women than men.

What Is Major Depressive Disorder?

As mentioned previously, depression has subtypes and depending on the severity there are classifications such as mild to moderate depression.

Major Depressive Disorder or Clinical Depression is a condition where the common symptoms of depression are pronounced and last for a long period.

The core symptoms by which Major Depressive Disorder can be diagnosed as identified by Diagnostic and Statistical Manual of Mental Disorders, 5th Edition are as follows (this list is prepared by clinicians and experts and has been directly taken from source):

Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

Note: Do not include symptoms that are attributable to another medical condition.

  • Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful).
  • Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day
  • Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day.
  • Insomnia or hypersomnia nearly every day.
  • Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down).
  • Fatigue or loss of energy nearly every day.
  • Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick).
  • Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others).
  • Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.

There are many other areas focused on DSM-V to help diagnose Major Depressive Disorder, but that is beneficial for clinicians and not applicable to us.

The presence of either 5 or more of the nine symptoms as mentioned above or even presence of depressed mood and lack of interest in daily life for a period longer than two weeks is diagnosed as Major Depressive Disorder.

However, these symptoms should not be caused by any other medical health condition or substances such as alcohol or medications.

Also these symptoms can occur in case of bereavement or grief of loss in which case a sound clinical judgement is required which is dependent on a person’s previous mental history.

How Common Or Prevalent Is Depression?

The lifetime prevalence of depression is as high as 20% in worldwide population, and observational studies suggest that male to female ratio is 5:2.

Almost 1 in 5 individuals will experience major depressive episode once in their life.

The most challenging aspect of depression treatment is that is a recurrent disorder. Most individuals recover from major depressive disorder, but as many as 75% of such individuals will experience a recurrence of depression with one episode of major depressive disorder in 10 years. And these figures are very alarming.

A significant proportion of individuals suffering from this condition land up developing chronic depression and even after a 5 or 10 year follow up (as part of observational studies) as many as 7-12% remain depressed.

Suicide is a significant risk factor for mortality in Major depressive disorder and suicide rate is high for the age group 15-24 years.

What Are The Types Of Depressive Disorders?

As mentioned previously, depression is identified as a heterogeneous condition. That typically means that there is not a condition that can be described by a particular set of symptoms; different individuals may present with different symptoms.

Primarily there are two major classifications:

  • Unipolar depression– Typically low mood over long time periods
  • Bipolar depression– Depressive periods with alternating periods of mania

As per ICD-10, the major categories are:

  • Mania episode
  • Bipolar affective disorder
  • Depressive episode
  • Recurrent depressive disorder
  • Persistent mood disorders (dysthymia, cyclothymia)
  • Other affective disorders
  • Unspecified mood disorders

Within unipolar depression, there are following categories:

  • Major depressive disorder ( single episode or recurrent disorder)
  • Dysthymic disorder

Also, depression based on severity and specific features can be further classified as:

  • Chronic depression
  • Depression with psychosis
  • Depression with atypical features
  • Depression on postpartum onset
  • Depression with anxiety
  • Premenstrual dysphoric disorder

What Causes Depression?

Causative factors behind depression differ with every individual. For some, it could be a particular trigger factor, and when exposed to that condition they may experience depression, for some it may be a major life event.

Interestingly some individuals experience depression from childhood without any triggering factor, and that manifests as major depressive disorder in later stages. Certain health conditions could also be responsible, mostly those that involve inflammation for example arthritis.

Substance abuse like alcohol could also cause depressionbe a causative factor. Fluctuation in hormones especially in females can trigger depressive behavior as in the case of premenstrual dysphoric disorder and postpartum depression.

Herein we will go through a couple of causes or risk factors for depression:

1. Stressful Life events

A stressful or negative life event is one of the most common causes or risk factor for rather major depressive episode. Most studies do highlight the fact that severely threatening events or negative events have been reported by depressed patients before the onset of the condition.

The nature of these problems differs; it could range from something personal like relationship issues to other aspects like occupational or financial issues.

Childhood abuse and even neglect during childhood are found to increase severity of depressive symptoms in later stages of life.

Men are found to experience depressive episodes in case of events such as divorce, separation, and occupation-related issues while women are affected by social events such as difficulty getting along with individuals, or a serious illness or death.

Ruminating on stressful events as well as increased sensitivity to stress is observed in individuals suffering from the major depressive disorder.

2.Genetic influences

Apart from the ‘It is all in your head!’ concept, there is an ‘It is in your genes!’ concept. And the unlike, the former this concept has been scientifically investigated.

Genetic links and inheritance are found to be as high as 80% in conditions like bipolar disorder and depression. Several genes interact with each other, and additionally, environmental factors may contribute to susceptibility to depression.

However, simply interaction of genes alone is not sufficient for the development of depression.

Genetic disturbances have been observed about genes responsible for neurotransmitter transport or synthesis in depression and bipolar disorder.

Influence of genetic factors on susceptibility to depression is somewhere around 30-40%.

However, inheritance of genetic links in depression is found to be more pronounced in women than men.

3. Certain Health conditions

Chronic health conditions may pave the way for depression especially in the case of chronic pain. For example in arthritis and lupus, some individuals present with depressive symptoms.

This could be a result of inflammation or due to the state of chronic illness which impedes one’s daily life and thus causing unhappiness, irritation and negative feelings.

Conditions that affect hormones and metabolism such as metabolic syndrome, diabetes, PCOS may also cause depressive symptoms.

Intake of certain medications like chemotherapy and anti-viral medications have been reported to induce depressive symptoms.

Depression Pathophysiology: What happens in your body in depression?

Research has been conducted about various aspects as to what exactly happens in the body when one is depressed.

1.Disturbances in brain chemicals- Monoamine hypothesis

Neurotransmitters or chemicals in the brain are responsible for communication between brain and nerve cells.

The first hypothesis of the cause of depression was a deficiency in a particular type of neurotransmitters called monoamine neurotransmitters.

Particularly these neurotransmitters include serotonin, dopamine, and noradrenaline. These chemicals control our behavioral symptoms ranging from appetite, motivation, energy levels, etc.

Therefore disturbance in synthesis, storage or transport of these neurotransmitters leads to disturbed mood states. Antidepressants act on these various aspects of neurotransmitters.

Most of the focus on treating depression is around the neurotransmitter ‘serotonin, ’ but researchers are even focusing on the role of ‘dopamine’ in antidepressant treatment.

There is quite a bit of debate as to whether this concept of depletion of neurotransmitters is responsible for depressive symptoms.

Some studies demonstrate that depletion of neurotransmitters do not increase depressive symptoms in those suffer from depression but do not take medications. It also does not cause depressive symptoms in healthy individuals.

Reduction in depressive symptoms on taking antidepressants indicate the involvement of these monoamine neurotransmitters in the occurrence of depression. This is not due to a single neurotransmitter but a result of a cumulative action of all neurotransmitters.

Apart from monoamines like serotonin and dopamine, there are other neurotransmitter systems that are essential for communication between brain cells.

GABAergic system is one of them (GABA -gamma-aminobutyric acid). Certain evidences point out the reduction in GABA concentration in major depression.

But contrary to expectations, treatment with medications that affect GABA levels are not found to have a superior antidepressant effect than conventional treatment.

Similarly, another neurotransmitter system called glutamate system is also found to be involved in this condition.

2.Disturbances in Growth factors in the brain- Neurotrophin hypothesis

Neurotrophin or neurotrophic factors are proteins that are essential for growth, development, and survival of neurons or brain cells.

Brain-derived neurotrophic factor (BDNF) is one such element that essential for healthy brain functioning.

It is suggested that the first depressive episode may be in response to a life event or social trigger while subsequent episodes may be induced internally- it may occur spontaneously or in response to minor stress.

Researchers suggest that this could be a result of brain volume loss and one of the reasons behind this loss could be decreased levels of neurotrophic factors such as BDNF.

Studies observe that reduced levels of BDNF could lead to depressive symptoms and BDNF levels are elevated in response to antidepressant treatment.

3.Hormonal fluctuations

Impairment in the secretion of hormones such as cortisol (stress hormone) and related parameters is found to be related to depressive symptoms. It is found that individuals with depression have increased secretion of cortisol which reduces upon treatment.

Women are more stress responsive than men which could suggest why women are more susceptible to depression.

Interestingly men show increased cortisol levels in response to an achievement while women have high cortisol levels in response to social rejection.

Similarly, disturbance in thyroid function has been linked with depression. Disturbance in sex hormones such as estrogen and progesterone may also contribute to postpartum depression.

4.Immunity and Inflammation

Immune function may be altered in depression which can lead to progression of the disorder. This could result in activation of an immune function or even suppression.

Studies have identified increased secretion of immune mediators and inflammation causing agents in depressed patients.

These inflammation causing agents is found to affect various aspects such as appetite, sleep, and cognition.

Increase in inflammation causing agents can affect the level of proteins that are required for survival and development of neurons (brain cells) and their healthy communication, thereby resulting in cell death and damage to brain cells.

5.Change in brain structure

Chronic stress is found to cause structural changes in the brain.

Studies have identified certain structural abnormalities in particular brain regions in individuals suffering from Major depressive disorder compared to healthy individuals.

These parts of the brain are found to be involved in pain sensation, aggression, sexual function, risk assessment, memory, etc. Therefore alterations in these areas of the brain could result in behavioral abnormalities.

6.Physical disturbances

Physical symptoms of depression can range from pain to gastrointestinal upset to appetite changes. Higher the number of physical symptoms more likely is the person to suffer from a mood disorder.

The more painful the symptoms, the more severe is the depression. Suicide rates are found to be higher in patients with chronic pain.

Pain and depression share a common neurological pathway. The same neurotransmitters that affect mood also affect pain sensitivity. That is why treatment with antidepressants is found to alleviate physical symptoms.

Apart from presenting with physical symptoms, it is important to note that depression can increase an individual’s risk of developing other diseases.

For example, depression increases the risk for cardiovascular disorders by 1.5-2 fold, for stroke by 1.8 fold, for Alzheimer’s Disease by 2.1 fold , for epilepsy by 4-6 fold, for diabetes by 60%, for cancer by 1.3-1.8 fold.

What Are The Medical Signs And Symptoms Of Depression?

Depression presents with different symptoms in different individuals (all may not show some or any of these symptoms), but some of these are common characteristics such as :

  • Low mood
  • Lack of interest in activities
  • Avoiding social contact
  • Increased or decreased appetite
  • Lack of sleep or increased sleeping pattern
  • Excessive weight loss or weight gain
  • Fatigue
  • Restlessness
  • Problem concentrating
  • Hopelessness
  • Lack of self-esteem or self-confidence
  • Feelings of guilt
  • Suicidal ideation

Depression can also present with somatic or physical symptoms such as

  • Chronic backache
  • Stomach spasms
  • Excessive episodes of Bloating
  • Chronic knee pain
  • Migraine or repeated episodes of headache
  • Aversion to food or heightened craving
  • Constipation
  • Gastric upset
  • GERD or acid reflux
  • Delay in menstrual cycle with heavy or little bleeding

Lesser known symptoms of depression include :

  • Disturbance in cognitive function such as verbal fluency or processing speed
  • Memory deficits
  • Sexual dysfunction
  • Anxiety and panic disorders
  • Phobias
  • Leaden paralysis
  • Rejection sensitivity

What Are The Treatment Options For Depression?

Quite a number of treatment strategies are being researched upon and developed for depression. Herein we will be going through a gist of mainstream treatment options.

Antidepressants or Pharmacotherapy

These are medications that particularly alter the concentration of neurotransmitters in the brain to relieve depressive symptoms. The major focus is on altering serotonin levels.

Newer drugs focussing on dopamine, glutamate, GABA, melatonin, and corticotrophin releasing hormones are being researched upon.

A time lag is noted between starting antidepressant treatment and achieving a response. Also since one single neurotransmitter is not responsible for depression and since it affects other systems as well, it is difficult to achieve remission with antidepressants alone.

Non-pharmacotherapy options

These are other treatment modules which do not involve any oral medications.

Psychotherapy: This typically involves counseling and other psychological techniques to interact and address causative factors like childhood adversity, or other stressful events.

Electroshock/Electroconvulsive therapy: This is an invasive procedure of stimulating the brain with electric currents and reversing symptoms of mental illness. Due to its invasive nature and possibility of causing amnesia, it is not used to treat depression.

Neurostimulation therapy: These include deep brain stimulation, transcranial magnetic stimulation, vagus nerve stimulation wherein specific parts of the brain are electrically stimulated. However, these are restricted only to patients who are resistant to conventional treatment.

Complementary and Alternative Medicine

This area has been actively gaining focus by patients as well as researchers in the treatment of depression.

Phytochemicals or plant-based compounds are being identified with unique antidepressant properties, and research is investigating their efficacy in real time treatment.

Herbal medicine, homeopathy, aromatherapy, etc. are few other treatment options. Mindfulness, mind-body techniques and traditional practices like yoga, tai-chi, acupuncture benefit in depression as well.


The most important aspect of depression is its heterogeneous nature; unlike other disorders, it does not fit into a particular mold and also it could present with overlapping symptoms with other disorders.

Since it does not present with overt physical symptoms at times, depression may go unnoticed.

Another crux of this condition is that depression is not a behavioral choice or pattern, and a variety of factors are responsible for it. As a result, one particular line of treatment does not always deliver the results. However, opting for therapy (natural or conventional) can help manage the health condition.




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