Are Anxiety and Depression the Same Across All Conditions? A Critical Examination

Psychiatrists rely on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to make diagnoses of conditions like anxiety. This manual uses a symptom-based approach that creates remarkably diverse diagnostic categories. Consider how someone can meet criteria for Generalized Anxiety Disorder (GAD).

One person might experience primarily somatic symptoms (muscle tension, restlessness, fatigue)
Another person might experience predominantly cognitive symptoms (worry, difficulty concentrating)
A third might present with mostly behavioral symptoms (irritability, avoidance)

Yet all three could receive the same diagnosis of GAD despite having potentially different underlying mechanisms. Similarly, for Major Depressive Disorder (MDD), the DSM-5 requires 5 of 9 possible symptoms, creating 126 different possible symptom combinations that all yield the same diagnosis.

Different Pathways to Similar Presentations
Recent research suggests these broad diagnostic categories may mask distinct conditions

• Neurobiological differences: Different neurotransmitter systems, circuits, and neuroinflammatory processes may underlie similar symptom presentations
• Context-dependent expressions: Similar symptoms may arise from different contexts (e.g., reactive vs. endogenous depression)
• Comorbidity patterns: How symptoms cluster with other conditions may provide clues to their underlying nature
• Treatment responses: Differential responses to interventions suggest heterogeneous mechanisms

Evidence From Neurodegenerative Conditions
We recently studied possible anxiety subtypes in Alzheimer’s disease (AD) with machine learning, providing compelling evidence for different subtypes. The finding that anxiety clusters differently in AD compared to Subjective Cognitive Decline (SCD) or Traumatic Brain Injury (TBI) suggests these symptoms, while phenotypically similar enough to be captured by the same scale, may have distinct underlying mechanisms.
The correlation between neuropsychiatric symptoms and amyloid burden, as well as microglial activation markers, points to specific biological processes that may generate anxiety symptoms in neurodegenerative disease that are fundamentally different from anxiety in other contexts.

Clinical Implications
If anxiety and depression are not uniform entities across different settings, this has important implications:

Diagnostic refinement: We may need more precise, mechanism-based diagnostic approaches rather than purely symptom-based ones
Treatment selection: Understanding the underlying mechanisms could guide more targeted interventions
Research methodology: Studies that lump all presentations of a disorder together may obscure important signals
Biomarker development: Different subtypes may require different biological markers for identification

Future Directions
The field appears to be moving toward a more nuanced understanding of these conditions. Future research might include:

Transdiagnostic studies: Examining symptom dimensions across diagnostic boundaries
Multimodal assessment: Combining clinical, neuroimaging, inflammatory, and genetic markers
Computational approaches: Using machine learning to identify patterns not obvious through traditional analyses
Treatment response studies: Using differential response to guide subtyping

Conclusion
The evidence increasingly suggests that anxiety and depression are not unitary constructs but rather collections of similar symptom presentations that may arise from distinct underlying mechanisms. The research on anxiety subtypes in neurodegenerative conditions provides a compelling example of how symptoms that appear clinically similar may have different neurobiological underpinnings.
This perspective invites us to reconsider our approach to these conditions, moving beyond broad diagnostic categories toward a more mechanistic understanding that could ultimately lead to more precise and effective treatments.