Pharmacological Treatment Patterns and Neurobiological Aspects of Trichotillomania

Definition: Trichotillomania (TTM) is a chronic psychiatric condition, classified as a hair-pulling disorder, characterized by recurrent pulling out of one's hair. This behavior leads to visible hair loss and significant psychosocial sequelae.
Demographics and Prevalence:
- General Prevalence: Estimated between $0.5\%$ and $2.0\%$ .
- Gender Gap: In adults, there is a substantial female predominance with a ratio of $4:1$ . However, during childhood and adolescence, the gender ratio is nearly equal.
- Age of Onset: Typically begins at a young age, with a peak onset between $10$ and $13$ years, regardless of cultural setting.
Body Locations Affected:
- Scalp: The most common site, preferred by $73\%$ of patients.
- Eyebrows: Observed in $56\%$ of cases.
- Pubic Region: Observed in $51\%$ of cases.
Triggers for Hair Pulling:
- Emotional: Anxiety, boredom, and anger.
- Cognitive: Rigid thinking, cognitive errors, and specific thoughts regarding one's hair.
- Sensory: Characteristics of the hair such as thickness, length, and location.

Psychosocial Impact: Individuals often experience intense shame, guilt, and embarrassment due to noticeable hair loss, which further impairs well-being. Hair pulling may serve as a mechanism to regulate emotional states through negative reinforcement during stressful events.
Personality Traits: Compared to healthy controls, individuals with TTM may exhibit higher levels of neuroticism and lower levels of extraversion and conscientiousness.
Comorbidities:
- Anxiety and OCD: Anxiety disorders (Generalized Anxiety Disorder and Social Anxiety Disorder) and Obsessive-Compulsive Disorder (OCD) are prevalent. The repetitive and compulsive nature of TTM suggests overlapping neurobiological mechanisms with OCD.
- Depression: Depressive symptoms frequently accompany the disorder, increasing the overall burden.
Neurobiology and Pathophysiology:
- Gray Matter: Neuroimaging studies have found reduced volumes of gray matter in the cerebellum, putamen, and frontal gyrus.
- White Matter: Research indicates reduced fractional anisotropy in white matter tracts associated with the somatosensory and motor cortex.
- Neural Circuits: These changes suggest disruptions in circuits responsible for generating/suppressing motor habits and regulating emotions.

Objective: To characterize real-world prescription patterns for TTM and compare them against expert-proposed therapeutic approaches.
Database: The TriNetX network, a worldwide federated research network providing access to electronic medical records (EMRs).
Cohort Identification: Patients were identified using the ICD-10 code $F63.3$ (Trichotillomania).
- European-Middle East-Africa (EMEA) Cohort (EC): Data from $16$ Healthcare Organizations (HCOs).
- United States Collaborative Network (USCN) Cohort (UC): Data from $60$ HCOs.
Isolated Trichotillomania Cohorts: Additional sub-cohorts were created to exclude patients with comorbid psychiatric disorders (e.g., depressive episodes, OCD, dementia, delirium) to isolate TTM-specific prescriptions.
Analysis Window: Prescription data were observed at the index event (diagnosis) and followed for up to $20$ years.

US Cohort ( $n = 109,741$ ):
- Gender: $51\%$ Male ( $55,616$ ), $47\%$ Female ( $51,881$ ).
- Age at Diagnosis: Mean $41.5 \pm 27.4$ years.
- Race: $63\%$ White, $16\%$ Black/African American, $2\%$ Asian, $19\%$ Unknown.
Isolated US Cohort ( $n = 41,407$ ):
- Gender: $59\%$ Male ( $24,622$ ), $39\%$ Female ( $16,160$ ).
- Age at Diagnosis: Mean $33.1 \pm 27.2$ years.
European Cohort ( $n = 1,275$ ):
- Gender: $56\%$ Male ( $716$ ), $44\%$ Female ( $558$ ).
- Age at Diagnosis: Mean $35.3 \pm 30.6$ years.
- Race: $97\%$ Unknown.
Isolated European Cohort ( $n = 1,062$ ):
- Age at Diagnosis: Mean $30.9 \pm 29.8$ years.

Benzodiazepine Prevalence:
- In both cohorts, benzodiazepine derivatives (sedatives/hypnotics) were the most frequently prescribed drugs.
- UC Post-Diagnosis: $36.6\%$ received benzodiazepines (primarily Lorazepam at $26.9\%$ and Midazolam at $18.4\%$ , implying overlap).
- EC Post-Diagnosis: $20.8\%$ received benzodiazepines.
- Isolated Cohorts: Even when excluding comorbidities, benzodiazepines remained high ( $22\%$ in EC; $10\%$ in UC).
Antipsychotic Use:
- Haloperidol: Prescribed to $19.3\%$ of patients in both the UC and EC post-diagnosis.
- Quetiapine: Prescribed to $15.1\%$ of patients in both cohorts.
- Olanzapine: EC post-diagnosis likelihood increased to $9.0\%$ .
Antidepressant and SSRI Usage:
- Usage of SSRIs, TCAs, and SNRIs was notably limited.
- Sertraline: $8.7\%$ in both cohorts post-diagnosis.
- Fluoxetine: EC post-diagnosis likelihood was $5.7\%$ .
N-acetylcysteine (NAC):
- EC Shift: The most notable change in the EC was the increase in NAC prescriptions from $0\%$ pre-diagnosis to $8.1\%$ post-diagnosis.
- UC Usage: Remained low at $2.7\%$ .

First-Line Recommendations (Expert View): Selective Serotonin Reuptake Inhibitors (SSRIs) such as fluoxetine, citalopram, fluvoxamine, and sertraline are suggested as primary therapeutic options.
Behavioral Therapy: Randomized Controlled Trials (RCTs) suggest that behavioral therapy or a combination of therapy and medication is more effective than SSRIs alone.
Atypical Antipsychotics:
- Olanzapine: Studied in a $12$ -week RCT; demonstrated a $66\%$ reduction in hair-pulling and a $63\%$ decrease in anxiety scores at a maximum dose of $10\,mg/day$ .
- Aripiprazole: Impacts dopamine signaling and neural reward pathways.
- Quetiapine: Often used as adjunctive therapy with fluoxetine.
- Haloperidol: Shown to be effective for patients who do not respond to SSRIs, often leading to complete remission.
Glutamate Modulators (N-acetylcysteine):
- Mechanism: Increases glutamate activity in the nucleus accumbens to reduce compulsive behaviors.
- Efficacy: Clinical improvement observed by week $9$ in adults. However, an RCT of $39$ children/adolescents showed no significant difference compared to placebo.

The Practical Gap: There is a striking difference between expert guidelines (which favor SSRIs and NAC) and real-world data (which show heavy reliance on benzodiazepines and haloperidol).
Possible Causes of Discrepancy:
- Lack of official international guidelines from the FDA or EMA.
- Dermatologists may use benzodiazepines as a "quick way" to address the visible anxiety associated with TTM.
- The disorder falls between dermatology and psychiatry, potentially leading to neglect by both specialties.
Study Limitations:
- Data is retrospective and dependent on accurate ICD-10 coding.
- Population-based studies may detect false positives due to high participant numbers.
- No data available on disease severity or clinical treatment outcomes.
Final Conclusion: There is an urgent need for standardized pharmacological care and better education for clinicians to bridge the gap between clinical research and real-world medical practice.