What is the major area of the brain involved in major depressive disorder (MDD) and what are the specific symptoms as outlined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria?

Major Brain Areas Involved in Major Depressive Disorder and DSM-5 Symptom Criteria

Primary Neural Circuits in MDD

The prefrontal-limbic network, consisting of the prefrontal cortex (particularly dorsolateral, dorsomedial, and ventromedial regions), anterior cingulate cortex, amygdala, and hippocampus, represents the core dysregulated circuit in major depressive disorder. 1, 2 This interconnected network is modulated by the hypothalamus, basal ganglia, and midbrain structures 2.

Specific Brain Regions and Their Alterations

Prefrontal Cortex:

• The dorsolateral prefrontal cortex (dlPFC), dorsomedial prefrontal cortex (dmPFC), and ventromedial prefrontal cortex (vmPFC) show functional and structural alterations in MDD 3, 1
• Under normal circumstances, the prefrontal cortex identifies environmental cues and inhibits sympathoexcitatory networks while maintaining control over subcortical structures including the amygdala 4
• In MDD, this top-down regulatory control becomes impaired, leading to disinhibition of limbic structures 4, 2

Hippocampus:

• The hippocampus demonstrates the most consistent structural changes, with volume reductions documented across multiple studies 1, 5
• Progressive hippocampal atrophy occurs with illness duration, mediated by glucocorticoids, inflammatory cytokines, and reduced brain-derived neurotrophic factor 3

Amygdala:

• Shows altered activation patterns and disrupted connectivity with prefrontal regions 1, 5
• The amygdala's hyperactivity contributes to negative emotional processing and fear responses when prefrontal inhibition fails 4

Additional Affected Regions:

• Anterior cingulate cortex: involved in emotional regulation and cognitive control 2
• Frontal lobe, temporal lobe, thalamus, and striatum all show significant structural alterations 5

Key Neural Circuits

Three primary circuits are disrupted in MDD:

1. Frontal-subcortical circuit: Impaired cognitive control and executive function 5
2. Affective-salience network: Dysregulated emotional processing involving amygdala-prefrontal connections 1
3. Cognitive control network: Altered working memory, planning, and emotion regulation 1

DSM-5 Diagnostic Criteria for Major Depressive Disorder

MDD requires at least 5 symptoms present during the same 2-week period, representing a change from previous functioning, with at least one symptom being either (1) depressed mood or (2) loss of interest or pleasure 6, 7:

The Nine Core Symptoms:

1. Depressed mood most of the day, nearly every day (subjective report or observation by others) 6, 7

2. Markedly diminished interest or pleasure in all or almost all activities most of the day, nearly every day (anhedonia) 6, 7

3. Significant weight change (loss or gain of more than 5% body weight in a month) or change in appetite nearly every day 6, 7

4. Sleep disturbance: insomnia or hypersomnia nearly every day 6, 7

5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings) 6, 7

6. Fatigue or loss of energy nearly every day 6, 7

7. Feelings of worthlessness or excessive/inappropriate guilt (which may be delusional) nearly every day 6, 7

8. Diminished ability to think or concentrate, or indecisiveness, nearly every day 6, 7

9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide 6, 7

Additional Diagnostic Requirements:

• The symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning 6, 7
• The episode is not attributable to physiological effects of a substance or another medical condition 6, 7
• The episode represents a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning 6, 7

Critical Distinction from Persistent Depressive Disorder:

MDD is characterized by discrete episodes lasting at least 2 weeks with interepisode remissions, whereas Persistent Depressive Disorder requires chronic symptoms for at least 2 years without meeting full MDD criteria 8. This temporal distinction is essential for accurate diagnosis 8.

Neurobiological Mechanisms Linking Brain Changes to Symptoms

The structural and functional alterations in the prefrontal-limbic network directly produce the symptom clusters seen in MDD:

• Hippocampal and prefrontal dysfunction → impaired cognitive function (concentration difficulties, slowed thinking) 3, 1
• Amygdala hyperactivity with reduced prefrontal control → dysregulated emotional processing (depressed mood, feelings of worthlessness) 4, 2
• Hypothalamic-pituitary-adrenal axis dysregulation → vegetative symptoms (sleep disturbance, appetite changes, fatigue) 1
• Disrupted reward circuitry involving ventral striatum and prefrontal cortex → anhedonia and loss of interest 5

These neurobiological changes are progressive, with longer illness duration associated with greater structural alterations, particularly hippocampal volume loss 3. This underscores the importance of early, comprehensive treatment aimed at achieving remission to prevent further neuroanatomical deterioration 3.