Stressors can induce depression and depressive-like behaviors in mouse models, and this is associated with changes in microglia, particularly in the frontal cortex and the hippocampus. Furthermore, in post-mortem analysis of suicides, imaging reveals abnormal densities (both increased and decreased) of microglia in both MDD patients and in other psychiatric patients relative to healthy controls.

Scripps College

Major depressive disorder is a type of depressive disorder characterized by distinct episodes involving deep sadness and a loss of interest or enjoyment in previously pleasurable activities, among other related symptoms.

Major Depressive Disorder

Microglial dysfunction has been implicated in psychiatric conditions, such as depression, anxiety, bipolar disorder, and schizophrenia. 
Some proposed mechanisms include:
-overexpression of inflammatory cytokines as a response to psychological stressors (may be especially important in suicidality)
-abnormal phagocytosis and synaptic pruning (too much), as well as adult neurogenesis (not enough)
-decreasing development of oligodendrocyte progenitor cells, which results in decreased myelination/white matter function (especially associated with depression)

Microglia and Psychiatric Disorders

Rahimian, R., Wakid, M., O’Leary, L.A., Mechawar, N., 2021. The emerging tale of microglia in psychiatric disorders. Neuroscience & Biobehavioral Reviews 131, 1–29.. doi:10.1016/j.neubiorev.2021.09.023

"The emerging tale of microglia in psychiatric disorders"

Treatment resistant depression is generally acknowledged as depression which has not responded to a minimum of two different antidepressant medications. It is fairly common, with 60-75% of depressed patients meeting this criteria with a high severity and duration and increased exhibition of physical and mental symptoms that lead to higher dysfunction.

Treatment Resistant Depression

A depression relapse is another episode of depressive symptoms that happens fewer than six months  after symptoms have alleviated and remission was achieved.

Depression Relapse

Sleep disturbances are symptoms of depression that can persist during an episode or after an episode concludes. These disturbances can be seen in increased sleep onset latency (insomnia), frequent awakenings or arousals, increased wake after sleep onset, increased light sleep (stage 1), less deep sleep (slow wave sleep, sleep stages 3 or 4), subjective restlessness or feeling of being unrefreshed upon waking

Sleep Disturbances in Depression

Microglia in Major Depressive Disorder

When a person is diagnosed with a physical chronic illness, due to the limitations caused as a result of pain, work absences, activity reduction, and temporary disabilities, there can be a co-morbid presentation of mental illnesses such as Major Depressive Disorder (MDD). 

Chronic Illness and Major Depressive Disorder

Different from a relapse, a recurrence is a new episode of depression that comes after six months of being treated and symptoms have been alleviated.

Depression Recurrence

Depression library

Exercise has widely been reported to enhance positive mood and reduce negative mood, based on self-reported questionnaires. The effects of exercise on mood is immediate and continues for about one day. Its benefits are maximized when subjects find the type of physical activity enjoyable.

Exercise and mood

Physical symptoms commonly presented in children diagnosed with Major Depressive Disorder include; achy stomaches, headaches, generalized pain, and gastrointestinal issues.

Common Physical Symptoms of MDD in Children

A significant comorbidity exists between obsessive-compulsive disorder (OCD) and major depressive disorder. Data shows that 41% of individuals with OCD also meet the diagnostic criteria for major depressive disorder. This relationship is often depicted in a Venn diagram, where the overlapping section of the two disorders' circles represents the percentage of co-occurrence.

Comorbidity of Obsessive-Compulsive Disorder and Major Depressive Disorder

The development of major depressive disorder is understood to be multifactorial, involving a combination of genetic, biological, and psychological explanations. Genetic research points to a heritable component, biological models often focus on neurotransmitter systems and brain structures, while psychological theories examine factors like cognitive patterns, life stressors, and learned behaviors.

Etiology of Major Depressive Disorder

An individual named Blake illustrates symptoms of a potential major depressive disorder. He experiences persistent crying, feelings of worthlessness and hopelessness, and a lack of energy so severe that he is unable to get out of bed.

Example of Major Depressive Disorder Symptoms

According to the DSM-5, Major Depressive Disorder is characterized by two primary symptoms. The first is a persistently depressed mood that is present for most of the day, almost every day, often manifesting as feelings of sadness, emptiness, or hopelessness. The second key symptom is a marked loss of interest and pleasure in activities that were previously considered enjoyable, such as hobbies, social events, or sports.

Defining Symptoms of Major Depressive Disorder (DSM-5)

An illustration of the loss of interest (anhedonia) seen in major depressive disorder is when an individual abandons hobbies they were once passionate about. For example, a person who was an avid tennis player might completely stop playing or showing any interest in the sport after developing the disorder.

Example of Loss of Interest in Major Depressive Disorder

A diagnosis of major depressive disorder requires that an individual experiences either a depressed mood or a loss of interest/pleasure in most activities for a minimum of two weeks. In addition to one of these core symptoms, the diagnosis also requires the presence of several other signs, which can include: significant weight changes (either loss or gain), sleep disturbances like insomnia or hypersomnia, observable psychomotor changes such as agitation (e.g., fidgeting, pacing) or retardation (e.g., slowed speech and movement), persistent fatigue, feelings of worthlessness or guilt, diminished ability to concentrate or make decisions, and thoughts of suicide.

Diagnostic Criteria for Major Depressive Disorder

Beyond the core symptoms of depressed mood and loss of interest, a diagnosis of major depressive disorder considers several other indicators. These include: significant changes in weight or appetite, sleep disturbances (insomnia or hypersomnia), observable psychomotor changes (agitation or retardation), persistent fatigue, feelings of worthlessness or excessive guilt, difficulty with concentration or decision-making, and recurrent thoughts of suicide.

Additional Diagnostic Symptoms of Major Depressive Disorder

Major depressive disorder is characterized by its episodic course, where symptoms reach their full intensity for a period before subsiding. While these episodes may extend for several months, about 70% of individuals recover within one year. Nevertheless, the disorder can have long-term consequences, with approximately 12% of individuals still showing significant impairment after five years. Furthermore, even among those who recover, many continue to experience minor, fluctuating symptoms over the long term.

Episodic Nature and Prognosis of Major Depressive Disorder

Major depressive disorder is a profoundly serious condition that severely diminishes an individual's quality of life. It can be incapacitating, leading to significant functional impairments such as an inability to attend work or school, the abandonment of career paths, and financial losses from lost wages. In some cases, the severity of the disorder necessitates hospitalization.

Life Impact of Major Depressive Disorder

A significant social consequence of major depressive disorder is discrimination. The majority of individuals with the disorder report experiencing such treatment, which in turn creates barriers to forming close relationships and pursuing opportunities in employment and education for which they are qualified.

Social Discrimination in Major Depressive Disorder

There is a significant link between major depressive disorder and physical health, particularly cardiovascular wellness. The disorder acts as a risk factor, increasing the likelihood of developing heart disease in otherwise healthy individuals. Furthermore, for patients who already have heart conditions, depression can lead to worse health outcomes.

Major Depressive Disorder and Cardiovascular Health

Major depressive disorder is so common that it is often called the 'common cold' of psychiatric disorders. Statistics from the U.S. indicate that each year, approximately 6.6% of the population experiences the disorder, while the lifetime prevalence, or the proportion of the population that will experience it at some point, is 16.9%.

Prevalence of Major Depressive Disorder in the U.S.

Research suggests that the higher prevalence of major depressive disorder among women compared to men is not merely a result of differences in reporting symptoms or seeking help. Evidence indicates that the gender disparity likely originates from a combination of biological factors and distinct environmental experiences related to gender.

Explaining Gender Differences in Major Depressive Disorder Prevalence

The lifetime prevalence of major depressive disorder shows significant variation across different parts of the world. The highest rates are typically found in North and South America, Europe, and Australia, whereas the rates are observed to be substantially lower in Asian nations.

Geographical Differences in Major Depressive Disorder Prevalence

Studies indicate that the prevalence rates for major depressive disorder are higher among younger age groups when compared to older ones. A possible reason for this trend is that individuals in younger cohorts may be more inclined to acknowledge and report their depressive symptoms.

Age-Related Differences in Major Depressive Disorder Prevalence

Several risk factors are linked to major depressive disorder. These include socioeconomic factors like unemployment (which also applies to homemakers) and earning an annual income below \$20,000. Other associated factors are demographic, such as living in an urban environment, or relational, like being separated, divorced, or widowed.

Risk Factors for Major Depressive Disorder

Major depressive disorder often co-occurs with other psychological conditions. Specifically, there is a high rate of comorbidity with both anxiety disorders and substance abuse disorders.

Comorbidity of Major Depressive Disorder with Anxiety and Substance Abuse Disorders

In the DSM-5, specifiers are not considered distinct disorders but are labels used to describe specific patterns of symptoms or the timing of their occurrence in major depressive disorder. They provide a more detailed clinical picture. Examples of these specifiers include patterns related to seasonal onset, postpartum onset, chronicity, and features that are atypical, melancholic, or catatonic.

DSM-5 Specifiers for Major Depressive Disorder

The association between major depressive disorder and suicide is exceptionally strong, to the extent that the presence of suicidal thoughts is a formal criterion for diagnosing the disorder. This inclusion highlights the inherent and significant risk of suicide associated with this condition.

Suicidal Thoughts as a Key Criterion for Major Depressive Disorder

Based on the information provided in the case study, evaluate whether the individual currently meets the full diagnostic criteria for a major depressive episode. Justify your conclusion by referencing the specific symptoms and the required duration for a diagnosis.

Evaluating Diagnostic Criteria

1. Steinert, C., Hofmann, M., Kruse, J., & Leichsenring, F. (2014). Relapse rates after psychotherapy for depression – stable long-term effects? A meta-analysis. Journal of Affective Disorders, 168, 107–118. https://doi.org/10.1016/j.jad.2014.06.043

2. Yavi, M., Lee, H., Henter, I. D., Park, L. T., & Zarate, C. A., Jr (2022). Ketamine treatment for depression: a review. Discover mental health, 2(1), 9. https://doi.org/10.1007/s44192-022-00012-3

3. Rost, F., Booker, T., Gonsard, A., de Felice, G., Asseburg, L., Malda-Castillo, J., Koutoufa, I., Ridsdale, H., Johnson, R., Taylor, D., & Fonagy, P. (2024). The complexity of treatment-resistant depression: A data-driven approach. Journal of Affective Disorders, 358, 292–301. https://doi.org/10.1016/j.jad.2024.04.093

4. Besharat, M. A., Nia, M. E., & Farahani, H. (2013). Anger and major depressive disorder: The mediating role of Emotion Regulation and anger rumination. Asian Journal of Psychiatry, 6(1), 35–41. https://doi.org/10.1016/j.ajp.2012.07.013

5. Jochmann, A., Gusy, B., Lesener, T., & Wolter, C. (2024). Procrastination, depression and anxiety symptoms in university students: a three-wave longitudinal study on the mediating role of perceived stress. BMC psychology, 12(1), 276. https://doi.org/10.1186/s40359-024-01761-2

References for MDD

Researchers examined 88 patients diagnosed with MDD and their emotional thought patterns using the Multidimensional Anger Inventory and the Anger Rumination Scale. They found significant positive correlations between anger, anger rumination, emotion regulation, and depression, proving that anger is closely related with depression and its symptoms.

Association with Anger and Anger Rumination

By collecting longitudinal data from university students, researchers discovered that procrastination resulted in a development of depression and anxiety symptoms. 

Procrastination and Depression

There is evidence that neuroinflammation plays a role in the pathology of bipolar disorder, but further investigation is necessary to determine whether or not microglia are involved in this. However, microglia do appear to be overactive in the context of BD during both the manic and depressive phases, and they under-produce BDNF, which is involved in synaptic plasticity. There is some gene expression that differentiates the microglial function in BD patients and those with schizophrenia, as well as differences in postmortem microglia expression in BD patients who died by suicide versus those who did not, with the non-suicide group expressing lower levels of microglia density. Typical mood stabilizer treatments (lithium and valproic acid) seem to act on microglia, but the mechanism is unknown.

Microglia in Bipolar Disorder

There is evidence of increased neuroinflammation and inflammatory cytokines in the CSF of schizophrenia patients within 5 years of onset, as well as increased microglia density in the dorsolateral prefrontal cortex. Abnormal microglia density in the temporal lobe seems to be consistent across all schizophrenia patients, but there appears to be some nuanced differences among different subtypes and among the brains of patients who died by suicide versus not. Antipsychotic exposure seems to impact microglial density and inflammation, but this is not yet well understood.

Microglia in Schizophrenia

There is some evidence of substance-mediated responses in microglia. In particular, alcohol, cocaine, and methamphetamine show evidence (sometimes conflicting, however) of microglia-mediated neuroinflammation. Microglia may also have a modulatory effect on synaptic pruning in the dopaminergic circuit, which is implicated in addiction.

Microglia in Substance Use Disorders

SSRIs appear to regulate the activation state of microglia in addition to their effects on the serotonergic system when studied in vitro. Fluoxetine (Prozac) and its metabolite, norfluoxetine, have been shown to induce apoptosis in microglia, which limits the amounts of neuroinflammation they can cause. There appear to be both direct and indirect (modulating amount of serotonin available to microglia, or changing the extracellular environment) mechanisms by which this is done. 

Effects of SSRIs on Microglia

Both typical and atypical antipsychotics appear to inhibit the release of pro-inflammatory cytokines and potentially promote regular neurogenesis in schizophrenia patients by decreasing oxidative stress. Studies of prenatal administration of some antipsychotics in mice models have demonstrated a decrease in psychosis-like behaviors in the offspring. Given that the microglial inflammatory mechanisms are particularly pronounced in schizophrenia, this is a particular area of interest for future pharmacological research.

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