Persistent Depressive Disorder Persistent Depressive Disorder Neurobiology & Etiology 2 — Questions and Answers
Question 1: Which genetic polymorphism is most consistently associated with increased vulnerability to depressive disorders including PDD?
- COMT Val158Met polymorphism
- 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) (Correct answer)
- APOE ε4 allele
- MTHFR C677T variant
Correct answer: 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4)
The 5-HTTLPR short allele reduces serotonin transporter efficiency and, particularly in interaction with life stress, increases risk for depressive disorders including PDD.
Question 2: Which environmental factor has the strongest evidence for increasing risk of developing persistent depressive disorder?
- Urban living
- Chronic psychosocial stress and early life adversity (Correct answer)
- High-altitude residence
- Rotating shift work schedules
Correct answer: Chronic psychosocial stress and early life adversity
Chronic psychosocial stress and early life adversity are the most robustly supported environmental risk factors, sensitizing the HPA axis and altering gene expression related to stress regulation.
Question 3: Dysfunction in which prefrontal-limbic circuit is most implicated in the chronic mood dysregulation characteristic of persistent depressive disorder?
- Prefrontal cortex–basal ganglia circuit
- Anterior cingulate cortex–amygdala circuit (Correct answer)
- Prefrontal cortex–cerebellum circuit
- Insular cortex–thalamic circuit
Correct answer: Anterior cingulate cortex–amygdala circuit
Reduced anterior cingulate cortex regulation over amygdala reactivity leads to prolonged negative affective states and impaired emotional regulation in PDD.
Question 4: What does the 'kindling hypothesis' propose regarding persistent depressive disorder?
- Early depressive episodes require major stressors, while later episodes arise with minimal external stress (Correct answer)
- Each episode increases resilience against future mood disturbances
- Genetic vulnerability diminishes with each successive episode
- Medication sensitivity decreases with illness duration
Correct answer: Early depressive episodes require major stressors, while later episodes arise with minimal external stress
The kindling hypothesis proposes that early depressive episodes are triggered by significant life stressors, but over time the neural circuits become sensitized so that episodes occur with progressively less provocation.
Question 5: What role does hyperactivity of the default mode network (DMN) play in persistent depressive disorder?
- It causes attention deficits by suppressing task-relevant networks
- It is associated with rumination and excessive negative self-referential thinking (Correct answer)
- It reduces connectivity between prefrontal and limbic areas
- It promotes hypervigilance to external threat cues
Correct answer: It is associated with rumination and excessive negative self-referential thinking
Hyperactivity of the DMN in PDD is linked to maladaptive rumination — repetitive, passive focus on distress and its meanings — which perpetuates and deepens depressive states.
Question 6: Which metabolic finding in frontal and limbic brain regions has been documented in neuroimaging studies of persistent depressive disorder?
- Hypoglycemia confined to the thalamus
- Dysregulated glucose metabolism, with reduced activity in prefrontal areas (Correct answer)
- Elevated metabolic activity throughout the limbic system
- No significant metabolic differences from healthy controls
Correct answer: Dysregulated glucose metabolism, with reduced activity in prefrontal areas
PET studies show reduced glucose metabolism in prefrontal cortical regions and altered activity in limbic structures, reflecting the neurobiological underpinnings of anhedonia and mood dysregulation.
Question 7: Which sleep architecture abnormality is most commonly observed in persistent depressive disorder?
- Increased slow-wave sleep and delayed REM onset
- Shortened REM latency and reduced slow-wave sleep (Correct answer)
- Complete absence of REM sleep cycles
- Increased total sleep time with fragmented NREM cycles
Correct answer: Shortened REM latency and reduced slow-wave sleep
Shortened REM latency (earlier onset of the first REM period) and reduced slow-wave sleep are hallmark polysomnographic features of depressive disorders including PDD.
Persistent Depressive Disorder Persistent Depressive Disorder Neurobiology & Etiology 2
Which genetic polymorphism is most consistently associated with increased vulnerability to depressive disorders including PDD?