Article summary with Major depressive disorder by Otte a.o. - 2016

What is major depressive disorder?

Major depressive disorder (MDD) is a disease characterized by a depressive episode lasting at least two weeks, with marked changes in mood, interest and pleasure, changes in cognition, and vegetative symptoms. It is twice as common among women as in men and it occurs in 6% of the total population worldwide every year. It increases the risk of diseases such as diabetes, heart diseases and strokes. It can also lead to death by suicide. The genetic contribution is probably 35%. MDD is associated with smaller hippocampal volumes and changes in either activation or connectivity of neural networks. The neurobiological systems that regulate stress are also altered, including the HPA axis, the autonomic nervous system and the immune system. 30% of people with depression do not recover after treatment.

Bullet Points

• Major depressive disorder (MDD) is a disease characterized by a depressive episode lasting for at least two weeks, with marked changes in mood, interest and pleasure, changes in cognition, and vegetative symptoms. It is twice as common among women as in men and it occurs in 6% of the total population worldwide every year. The median age of onset is 25 years. It increases the risk of diseases such as diabetes, heart diseases and strokes. It can also lead to death by suicide. 30% of people with depression do not recover after treatment and 80% experience a relapse.

• The genetic contribution is probably 35%. MDD is associated with smaller hippocampal volumes and changes in either activation or connectivity of neural networks. The neurobiological systems that regulate stress are also altered, including the HPA axis, the autonomic nervous system and the immune system. There are also abnormalities in the affective-salience circuit and less activity in reward-related brain areas. There is increased activity in the default mode network, which contributes to excessive self-focus and rumination. Finally, there is hypo-connectivity in the frontoparietal cognitive control circuit, resulting in deficits in goal-directed attention.

• Depressive symptoms might be induced by disruptions of neuroplasticity and neurogenesis, for example there are lower levels of brain-derived neurotrophic factor. It has been known for years that monoamines are involved in depression. Both tricyclic antidepressants (TCAs) and monoamineoxidase inhibitors (MAOIs) have clear effects on monoamine neurotransmitters.

• First-degree family members of people with depression have a three times greater risk of developing depression. There is genetic overlap between depression and schizophrenia and bipolar disorder. 

• Stressful events are also related to depression, as well as adverse childhood events. Stress at a young age causes an increase in activity of neural circuits that contain corticotropin-releasing hormone. Stress in the womb also increases the risk of depression later in life.

• Severity of depression can range from mild to moderate to severe. Specifiers for more specific diagnosis are: with anxious distress, mixed features, melancholic characteristics, with atypical features, with psychotic traits and with catatonic traits. Prevention of depression can be achieved by strengthening protective factors or tackling symptoms in a prodromal stage.

• There are two treatment options: psychotherapy and pharmacotherapy. In general, moderate to severe depression is treated with medication or a combination of therapy and medication. A mild depression can usually be treated with only psychotherapy. The risk of relapse is smaller after psychotherapy. SSRIs and SNRIs are used more than TCAs because they have fewer negative side effects. The effectiveness is approximately the same for all types of antidepressant: 50%. 

• Treatment-resistant depression (TRD) is common in clinical practice (50-60%). In these cases it is important to assess medical and psychiatric comorbidity. Treatment methods for TRD are 1) psychopharmacological approaches, which use a combination of antidepressants or a combination of an antidepressant with another drug, or medication in high doses, 2) psychotherapy, mainly cognitive behavior therapy, 3) electroconvulsive therapy (ECT). However, ECT often leads to amnesia.

• Depression can lead to impairments in functioning at work, in families and in cognition. The cognitive areas that are affected include executive functioning, memory and attention. The risk of suicide is 20 times greater in depression than in the general population.

What is major depressive disorder?

Major depressive disorder (MDD) is a disease characterized by a depressive episode lasting at least two weeks, with marked changes in mood, interest and pleasure, changes in cognition, and vegetative symptoms. It is twice as common among women as in men and it occurs in 6% of the total population worldwide every year. It increases the risk of diseases such as diabetes, heart diseases and strokes. It can also lead to death by suicide. The genetic contribution is probably 35%. MDD is associated with smaller hippocampal volumes and changes in either activation or connectivity of neural networks. The neurobiological systems that regulate stress are also altered, including the HPA axis, the autonomic nervous system and the immune system. 30% of people with depression do not recover after treatment.

What is the epidemiology?

Depression occurs in 1 out of 6 adults. The prevalence appears to be independent of the income of a country. The discrepancy between countries is evident in terms of available resources and treatments. After puberty, women are twice as likely as men to develop depression. The median age of onset is 25 years. The absence of a partner and recent negative life events are determinants of depression. A range of social determinants as well as low educational attainment significantly increase the risk of depression. People who have experienced a childhood trauma have a more than twice as high risk of depression, with more severe symptoms, poorer course and worse treatment outcomes. The course of a depression is also worse if there are more serious symptoms or psychiatric comorbidity. An average episode lasts between 13 and 30 weeks. The chance of a relapse after a depressive episode is 80%. The contribution of depression to overall mortality is 10%.

What causes major depressive disorder?

How heritable is depression?

There is not one mechanism that can explain all facets of the disorder. First-degree family members of people with depression have a three times greater risk of developing depression. There is genetic overlap between depression and schizophrenia and bipolar disorder. Many genes with small effects are involved.

What is the effect of stress?

Stressful events as well as adverse childhood events (including abuse, neglect, exposure to domestic violence or early divorce of parents) are related to depression. Stress at a young age causes an increase in activity of neural circuits that contain corticotropin-releasing hormone. Stress in the womb also increases the risk of depression later in life.

Which gene-environment interactions are associated with depression?

There are gene-environment interactions associated with depression, and they might involve epigenetic regulation. Changes in the HPA axis are associated with impaired cognitive functioning and are more common in severe depression and in the elderly with depression. Antidepressants lower the cortisol level over the course of treatment, but a meta-analysis showed that cortisol levels are the same before and after treatment in 50% of the cases. The evidence of HPA axis changes has not yet led to new therapeutic avenues. Studies show that inflammatory mechanisms can also play a role in depression. This is due to peripheral cytokines that affect the central nervous system. Depressive symptoms might be induced by disruptions of neuroplasticity and neurogenesis, for example there are lower levels of brain-derived neurotrophic factor. It has been known for years that monoamines are involved in depression. Both tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) have clear effects on monoamine neurotransmitters. However, it is remarkable that although medication affects these neurotransmitters a few hours after taking the medication, antidepressant effects only become visible after a few weeks.

Which brain structures are altered in people with depression?

Hippocampal volume is reduced in people with depression, but the question is whether this is already present in a first depressive episode or whether it develops later. Moreover, abnormalities have been found in the affective-salience circuit, which is a central part in guiding motivated behavior. This mainly concerns an overactive amygdala, anterior cingulate and anterior insula. On the contrary, there is less activity in reward-related brain areas, such as the ventral striatum. There is also increased activity in the default mode network, which contributes to excessive self-focus and rumination. Finally, there is hypoconnectivity in the frontoparietal cognitive control circuit, resulting in deficits in goal-directed attention.

Which diagnostic criteria are used for depression?

Important differential diagnoses of depression are with bipolar disorder, persistent depressive disorder (depressive symptoms longer than 2 years), and schizophrenia. If the diagnosis of depression has been made, specifiers can be used, with the first being the severity. The severity can range from mild to moderate to severe. The second specifier is 'with anxious distress', and was introduced because patients with this specifier are more likely to report suicidal thoughts and have a less positive response to antidepressants. The 'mixed features' specifier indicates that during a depression there may also be symptoms on the other side of the spectrum that are associated with mania/hypomania. The 'melancholic characteristics' specifier includes the criteria anhedonia, lack of pleasure, loss of reactivity to positive stimuli, depression worse in the morning, waking up early, psychomotor disturbance, weight loss and excessive guilt. The 'with atypical features' specifier refers, among other things, to mood improvement in response to positive events, weight gain or increase in appetite and/or increased sleep. Finally, there are specifiers for psychotic and catatonic traits.
Given the high burden of disease of MDD, prevention is important and can be achieved by strengthening protective factors, or tackling symptoms in a prodromal stage.

What treatment options are used?

There are two treatment options: psychotherapy and pharmacotherapy. In general, moderate to severe depression is treated with medication or a combination of therapy and medication. A mild depression can usually be treated with only psychotherapy. However, the preferences of the patient and treatment history must always be taken into account. Studies have shown that psychotherapy is effective, and that there are no major differences between different forms of psychotherapy. The effects of psychotherapy are similar to those of medication, but the risk of relapse is smaller after psychotherapy. Psychotherapy by telephone has also proven to be effective, and drop-out levels are lower. Group therapy is also an effective and cost-efficient form of therapy. Treatments via the internet, with coaching via the telephone, are also effective and are increasingly being used.

What medication is used?

Antidepressants that act on monoamine neurotransmitters cause a neural response, and affect synaptic plasticity and gene expression. However, the precise way it works is still unknown. Nowadays, SSRIs and SNRIs are used more than TCAs because they have fewer negative side effects. The effectiveness is approximately the same for all types of antidepressant: 50%. Recently, antidepressants that are not based on monoamines are also being looked into. Several studies have shown that treatment with psychotherapy and medication is more effective than monotherapy.

What options are available for treatment-resistant depression (TRD)?

TRD is a form of depression that does not respond to at least one antidepressant. It is common in clinical practice (50-60%). In these cases it is important to assess medical and psychiatric comorbidity. Variables associated with treatment-resistant depression are old age, marital status, long duration of the current depressive episode, moderate to high suicidal risk, comorbidity with anxiety, multiple admissions, and comorbid personality problems. Treatment methods for TRD are 1) psychopharmacological approaches, which use a combination of antidepressants or a combination of an antidepressant with another drug, or medication in high doses, 2) psychotherapy, mainly cognitive behavior therapy, 3) electroconvulsive therapy (ECT). ECT is the most effective and most widely used form of a non-pharmacological biological treatment for depression. However, it often leads to anterograde and retrograde amnesia. New treatments for TRD include repetitive transcranial magnetic stimulation (rTMS), deep TMS, magnetic attack therapy (MST), vagnus nerve stimulation (VNS) and deep brain stimulation (DBS). However, rTMS is less effective than ECT. New pharmacological treatments for TRD are treatment with ketamine or esketamine, antagonists of NMDA.

What is the quality of life for people with depression?

Depression can lead to impairments in functioning at work, in families and in cognition. The cognitive areas that are affected include executive functioning, memory and attention. There is an attentional bias towards negative information. There may also be impairments in psychomotor speed. The deficits in executive functions and memory can be permanent. Neurocognitive impairments are negatively associated with psychosocial functioning. The risk of suicide is 20 times greater in depression than in the general population. Antidepressants do not seem to reduce the risk of suicide, but this also depends on age.

Which issues should the future address?

Given the fact that depression is prevalent worldwide, the highest priority is to ensure effective treatments in low-income countries. Future research should focus on the interplay between the human genome and environmental factors. Research should also focus on distinguishing subtypes of depression so that specific treatments can be developed.