Do neurosteroids produced by 5-alpha-reductase (5AR) mainly affect mood or cognitive ability in patients, particularly those with a history of neurological or psychiatric conditions or those taking medications like finasteride (5AR inhibitor)?

Neurosteroids Produced by 5α-Reductase: Primary Effects on Mood vs Cognitive Ability

Neurosteroids produced by 5α-reductase (5AR) primarily affect mood rather than cognitive ability, with the most robust evidence demonstrating consistent associations with depression and anxiety, while cognitive effects remain less well-established and potentially secondary to mood disturbances. 1, 2, 3

Primary Effects: Mood Disturbances

Depression Risk

• 5AR inhibitors (finasteride and dutasteride) are associated with a 61-68% increased risk of depression, with hazard ratios of 1.61 for finasteride and 1.68 for dutasteride compared to non-users 2
• This depression risk remains constant over time with continuous exposure, unlike dementia associations which decrease with prolonged use 2
• The mechanism involves decreased levels of neurosteroids with anxiolytic and neuroprotective properties, particularly allopregnanolone and tetrahydrocorticosterone 1, 3

Neurosteroid Alterations in Mood Regulation

• 5AR-produced neurosteroids have neurotrophic, neuroprotective, and anxiolytic properties that are critical for emotional regulation 1
• Patients with post-finasteride syndrome show decreased CSF levels of pregnenolone, progesterone, dihydroprogesterone, and dihydrotestosterone, all of which influence mood 4
• Reduced 5α-reductase activity has been directly observed during depressive illness in humans, establishing a clear mechanistic link 1

Clinical Manifestations

• In post-finasteride syndrome patients, 50% (8 of 16) met DSM-IV criteria for major depressive disorder 4
• Animal studies demonstrate that finasteride robustly induces anxious and depressive behaviors in rodents 1

Secondary Effects: Cognitive Function

Evidence for Cognitive Impact

• Cognitive complaints are reported in post-finasteride patients, but these occur alongside depression and anxiety, making it difficult to separate primary from secondary effects 4
• The association with all-cause dementia shows decreasing magnitude over time (HR 1.22 for finasteride, 1.10 for dutasteride), suggesting detection bias rather than true causation 2
• Alzheimer disease and vascular dementia associations become statistically nonsignificant with continuous exposures over 4 years, further supporting that cognitive effects are not the primary impact 2

Neuroplasticity Mechanisms

• Finasteride treatment causes reversible reduction in hippocampal neurogenesis (newborn cells and young neurons), which returned to normal 35 days after treatment cessation 5
• While hippocampal neurogenesis is linked to both emotional behavior and memory, the reversible nature and temporal pattern suggest mood effects are more clinically relevant 5

Mechanistic Pathways Supporting Mood Predominance

Multiple Converging Mechanisms for Mood Effects

• Alteration in neuroactive steroids (primary mechanism) 3
• Dopaminergic dysfunction affecting reward and motivation pathways 3
• Increased neuroinflammation contributing to depressive symptoms 3
• Alteration of the HPA axis (hypothalamic-pituitary-adrenal) affecting stress response 3
• Epigenetic modifications potentially causing persistent changes 3

Clinical Implications for 5AR Inhibitor Use

Risk Communication

• Prescribing clinicians should specifically counsel patients about depression risk when initiating finasteride or dutasteride 2
• The depression association is constant over time, unlike other neuropsychiatric effects that may diminish 2
• Patients with pre-existing neurological or psychiatric conditions warrant heightened monitoring for mood changes 6

Important Caveats

• 5AR inhibitors are not associated with completed suicide (HR 1.22,95% CI 0.99-1.49 for finasteride; HR 0.98,95% CI 0.62-1.54 for dutasteride), despite depression associations 2
• The magnitude of mood effects is clinically significant, unlike the modest sexual dysfunction effects which show only 3.21-point differences on 0-100 scales 6
• Drug-induced 5AR blockade is recognized as a cause of hypogonadism with associated psychological symptoms 6