REVIEW

Review of available studies of the neurobiology and

pharmacotherapeutic management of trichotillomania
Jacklyn Johnson, Abir T. El-Alfy *
Department of Pharmaceutical Sciences, Chicago State University, Chicago, IL 60628, USA
GRAPHICALABSTRACT
ARTICLEINFO
Article history: Received 12 January 2015 Received in revised form 5 May 2015 Accepted 20 May 2015 Available online 10
June 2015
ABSTRACT
Trichotillomania (TTM) is a psychiatric disorder characterized by an irresistible urge to pull out one’s hair. Currently there are no
FDA approved treatments for TTM, which makes it difficult for clinicians to select an appropriate therapeutic plan. The clinical
studies that have been performed do not provide sufficient or consistent evidence regarding which drug classes should be
administered. Unfortunately, most of the available data consist of case reports and clinical trials with limited sample size. This
review provides an overview of currently available clinical
*
Corresponding author. Tel.: +1 773 821 2598; fax: +1 773 821 2595. E-mail address: ael-alfy@csu.edu (A.T. El-Alfy). Peer
review under responsibility of Cairo University.
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Cairo University
Journal of Advanced Research
Keywords: Trichotillomania (TTM) Neurobiology Rating scales Clinical trials
Abir T. El-Alfy is an Associate Professor of Pharmaceutical Sciences and is a graduate of the Faculty of Pharmacy, Cairo
University, Egypt. She has a Master Degree in Microbiology, and a Ph.D. in Pharmacology and Toxicology from the University
of Mississippi. She was an Assistant Professor at King Saud University; an Assistant Professor, as well as the Director of the
Behavioral Neuroscience Core-NPN at the School of Pharmacy, University of Mississippi. She has published numerous research
papers in peer reviewed journals. She holds two patents; one on developing indole compounds as antide- pressant medications,
and another on the anxiolytic actions of pterostilbene.
Introduction
Originally described by Hallopeau in 1889, trichotillomania (TTM) is a psychiatric disorder that is characterized by the
incontrollable urge to pull out one’s hair [1]. The preferred term for this condition is ‘‘hair pulling disorder’’, as the word
‘‘trichotillomania’’ may be perceived with a negative connota- tion [2]. It is currently classified under ‘‘Obsessive Compulsive
and Related Disorders’’ in the Diagnostic and Statistical Manual of Mental Disorders, DSM-V [3]. Diagnostic criteria include the
following: continuously pulling out one’s own hair, which results in hair loss, multiple attempts to reduce or stop the hair pulling,
clinically significant impairment in daily func- tioning (e.g. social gatherings, work), the hair pulling is not associated with
another medical condition, and it cannot be explained by another mental disorder [3]. Previously in DSM-IV, TTM was classified
under impulse control disorders (not classified elsewhere). Diagnostic criteria included an increasing sense of tension right before
pulling out the hair or when resisting the urge, and pleasure, gratification, or relief
170 J. Johnson and A.T. El-Alfy
Jacklyn Johnson is a pharmacist. She got her Pharm D from Chicago State University in May 2015. Her research interests focus
on neuropsychiatric disorders, particularly tri- chotillomania and the development of new medications for its management.
literature that targets TTM. A summary of clinical trials as well as case reports is provided. The most common rating scales used
for clinical assessment are also reviewed. The etiology of TTM remains unclear. Studies that examine various neuroanatomical,
neurobiologic, as well as genetic factors associated with TTM are thoroughly discussed in this review. It is evident that clear
understanding of TTM is crucial to provide better recognition, assessment, and treatment to patients of this disorder. Finally,
despite research efforts for establishing pharmacological options for treatment, it is clear that new targets are warranted in order
to ensure a clinically supported effective pharmacological approach to treat TTM.
© 2015 Production and hosting by Elsevier B.V. on behalf of Cairo University.
when pulling out the hair [2]. As seen, this criterion was left out of DSM-V as not all TTM sufferers experience these occur-
rences. Christenson et al. [1] described TTM sufferers as either being aware or unaware of the hair pulling, or a combination of
both. These observations led to the TTM subtypes/styles known as focused and automatic, respectively. Automatic hair pulling
usually occurs during sedentary activities such as lying in bed, watching TV, or reading. Focused hair pulling, on the other hand,
occurs when hair is intentionally pulled out possi- bly by searching for specific hairs to pull out. This more focused pulling may
allow the individual to distract themselves from unwelcomed thoughts or feelings [4]. TTM has a lifetime prevalence of 0.6%
(according to DSM-III-R) for both gen- ders. However, Christenson et al. [1] concluded that for females the prevalence may be
as high as 3.4% and 1.5% for males. Sufferers typically pull from the scalp, eyebrows, and eyelashes but may also pull from the
face, axillary, and pubic regions [1,5]. Some individuals participate in hair-related ritu- als or behaviors once the hair is pulled
out. These could include rolling the hair between finger, running the hair over the lips or through the teeth, biting the hair, and/or
swallowing the hair (trichophagia). Others reported pulling out specific hairs based on characteristics such as texture, color, and
length [5]. The average age of onset occurs around 13 years, which coincides with puberty [6].
TTM has also been thought to relate to, or overlap with other psychiatric disorders including obsessive compulsive dis- order
(OCD), Tourette’s, and other impulsive disorders such as nail biting and skin picking [1,2,7]. This overlap is seen in TTM’s
symptomatology including similar ritualistic behavior and trigger cues as seen in body-focused repetitive behavioral disorders
(BFRBD) [2]. The similarities observed between TTM and OCD include behaviors in response to urges, anxiety relief after
performing the behavior, and the repetitive nature of the disorder [2]. Similarities with OCD also extend into the treatment
modalities used. According to Christenson et al. [8] the lifetime prevalence of comorbid psychiatric disor- ders in TTM patients
was found to be as high as 81%, with depression and anxiety subsequently reported as main con- tributing comorbid disorders to
TTM. TTM is a poorly under- stood disorder. Behavioral therapy has proven effective in many TTM patients; however, the use
of pharmacotherapy might be necessitated in some patients. Some individuals with TTM may respond to pharmacotherapy with
selective sero- tonin reuptake inhibitors (SSRIs), as do those with OCD [2]. Limited knowledge exists regarding the
neurobiological basis of TTM. However, it is speculated that the disorder probably involves multiple pathways and a complex
interac- tion between genetic, psychological, and social factors.
Studies suggest changes in reward processing and impulse con- trol, with the neurotransmitters serotonin, dopamine, as well as
GABA implicated in TTM [9]. Few brain imaging and genetic studies have reported gray matter density differences in various
brain regions in TTM patients as compared to con- trols [10–12]. The contribution of genetic factors has gained research attention
in the past decade, with reported mutations in SLITRK1 and HOXB8 genes in TTM patients and experi- mental animal models,
respectively [13–15]. The current review provides an overview of available studies that examined the neurobiology and potential
genetic determinants of the disor- der as well as summarizes available literature regarding reported clinical studies/cases of
various pharmacotherapeutic approaches. Future research directions that are needed for understanding and management of this
disorder are identified.
Methods
A literature search was conducted using PubMed and Google Scholar. The search spanned the period between 1989 and February
2014. Key words, and their combinations, used for the search were trichotillomania, hair pulling, hair pulling dis- order, clinical
trial, case report, neurobiology, genetic, and ani- mal model. A total of 875 potentially relevant articles were identified. The titles
and abstracts of the articles were screened, and 712 were excluded. Excluded articles were clinical reviews as well as articles
related to trichobezoar reports focused on surgical treatment. The abstracts of the remaining 163 articles were further examined,
and 108 articles were excluded. Exclusion criteria were non-English language of the article, clinical trial of behavioral therapy
approaches alone, and duplicates. The remaining fifty-five full text articles were retrieved and included in this review, and
thirteen articles investigated the neurobiology, animal models, and genetic aspects of TTM, while the remaining forty-two
articles focused on scoring scales and pharmacotherapeutic approaches of TTM. The latter included both clinical trials as well as
case reports.
Neurobiology of trichotillomania
Although TTM is classified according to DSM-V under obses- sive compulsive and related disorders, the classification of TTM
still remains controversial. As mentioned earlier, behav- ioral therapeutic approaches have proven to be more effective than
pharmacotherapy in most patient cases. However, some patient might require pharmacologic intervention. As will be evident in
later sections, pharmacotherapeutic approaches to treating TTM include a wide variety of drug classes, primarily antidepressants.
So far, the FDA has not approved any phar- macological treatment for TTM. Such lack of solid pharma- cotherapeutic
approaches might be partly attributed to our deficient understanding of the etiology and neurobiology of the disorder. Current
research has focused on neuroanatomical studies that attempt to unravel any brain abnormalities that might correlate with the
symptoms of TTM. Grachev [10] used MRI-based morphometric topographic parcellation to study the differences in the human
neocortex of 10 females with tri- chotillomania compared to 10 females without (TTM). In this study, researchers were interested
in investigating volumetric
Trichotillomania clinical studies and neurobiology review 171
changes of the sensorimotor cortex, supplementary motor cor- tex (juxtaparacentral lobule cortex) and operculum between TTM
and TTM-free participant. The study included 10 right-handed females with TTM that met DSM-IV criteria for TTM, and did not
have OCD, Tourettes, psychosis, major depression, substance abuse or significant medical or neurolog- ical illnesses. The 10
female controls were also right-handed and were similar in age and educational background. All sub- jects had to have normal
CBC, coagulation, and thyroid tests. Control subjects though did not have a psychiatric, neurologic, and physical examination.
All 20 patients were free of psy- choactive medications for at least 4 weeks. The average age of TTM patients was 31.1years and
28.5years in control patients. Researchers used MRI scans for brain images and a standard 3-D brain coordinate system was used
for positional normalization. Statistically significant volumetric differences were found between the TTM patients and control
groups in the left inferior frontal gyrus, triangularis division, and the right cuneal cortex. The volume of the triangularis division
was reduced by 27% while the right cuneal cortex was increased by 40%. There were no statistically significant differ- ences in
the total cerebral cortex volume. The increase in the right cuneal cortex in TTM patients may stem from failure of interactions
between the visual and sensorimotor cortices that cause increased neuronal stimuli to reach targets leading to the repetitive or
compulsive behavior seen in TTM [10]. Chamberlain et al. [11] investigated gray and white matter abnormalities in terms of the
whole brain in 18 individuals with TTM as compared to 19 healthy individuals. Participants were medication-free for >6 months
and had no previous diagnosis of depression or OCD. However, patients with TTM showed significantly higher Montgomery-A
̊
sbery Depression Rating Scale (MADRS) scores and dysphoric
mood compared to healthy volunteers but neither demon- strated clinically significant depression in regard to the MADRS score.
Significant differences were found in terms of increased gray matter density in 3 clusters. These consisted of the striatum (left
putamen) and left amygdalo-hippocampal complex, bilateral frontal regions (cingulate, supplemental motor and superior cortices)
and the left occipital and parietal regions. No significant differences were reported in white mat- ter density. The findings of
Chamberlain et al. [11] add more evidence that link TTM and OCD together. Increased gray matter has been reported in studies
of OCD. The increased gray matter may be due to neuroplastic changes that occur when using brain regions involved in
grooming, habit- learning and motor skill training. Dysfunction or abnormali- ties of the striatum, which is involved in habit
learning and automated action sequences, may disrupt the ability to per- form choreographed grooming sequences. This finding
impli- cates the role of the basal ganglia in the development of pathological habits. The abnormalities seen in the cingulate and
prefrontal lobes could be responsible for cognitive issues seen in TTM patients. The abnormalities found in the amygdalo-
hippocampal region may cause the arousal and emotional learning differences seen in hair pulling episodes. This study provides
baseline differences seen in different brain regions of TTM patients. Some of the findings are inconsistent with other available
literature which leads to the need of future studies that include more patients (including left-handed indi- viduals to see whether
there are differences in implicated brain regions), screening not only for depression but also for anxiety,
and the inclusion of using cognitive tasks simultaneously with the neuroimaging. Other researchers have shown that neurons
found in the anterior dorsolateral regions of the caudate–puta- men are activated during grooming movements [16]. The graphical
abstract summarizes the brain regions implicated in the pathology of TTM.
A recent study by Odlaug et al. [12] examined impaired response inhibition and cortical thickness in TTM patients, their
unaffected first degree family members, and control sub- jects. The study reported a significant impairment of response inhibition
performance in TTM patients as compared to con- trols. In addition, a significant increase in cortical thickness was observed in
TTM patients and their relatives compared to controls. The areas affected by the change were primarily localized in regions
controlling response inhibition including the right inferior/middle frontal gyri, left precuneus, left supe- rior temporal cortex, and
right lingual gyrus.
Although TTM is currently classified under obsessive com- pulsive and related disorders, previous research has focused on its
relevance to impulse control disorders (ICDs). Extensive research has been conducted that focused on neurobiological role of
various neurotransmitters in the pathology of ICD and their relevance to TTM. Serotonin (5-HT) has been impli- cated in OCD as
well as ICD because of its role in impulse con- trol as well as repetitive motor behaviors. Animal studies have previously shown
that serotonin depletion leads to impulse choices and motor behavior [17,18]. The activation of seroton- ergic systems using
SSRIs has been explored as a treatment option for TTM patients. However, as seen in later sections of the review, data from
various clinical studies and case reports show mixed results and the efficacy of SSRIs for TTM treatment remains unclear.
Dopaminergic systems are implicated in both OCD and ICD. The use of antipsychotic agents that block dopaminergic D2
receptors has been effective in the management of a subset of TTM patients, as discussed in later section [19–21]. The inhibitory
neurotransmitter GABA has been functionally and anatomically connected to dopaminergic systems. A retrospective study by
Nikolaus et al. [9] demonstrated regulation of dopamine by both GABA and 5-HT neurotransmitters in pooled patients with OCD
and anxiety disorders. Both GABA and 5-HT exert inhi- bitory effect on dopamine, and their reduction leads to enhanced
dopaminergic activity in the mesolimbic system, playing a role in the development of anxiety and obsessive compulsive disorders
[9]. The recent studies that demonstrated efficacy of the glutamate modulator N-acetylcysteine (NAC) in TTM patients have
drawn research attention to the role that glutamate might play in the pathophysiology of TTM [22,23]. It is evident that data
available so far suggest that a com- plex interaction between various neurobiological systems might play a role in the
pathophysiology of TTM, and further studies are certainly warranted.
Genetics studies
In addition to neuroanatomical studies, research efforts have also emphasized the role of genetics in TTM. Abelson et al. [13]
reported a 1 bp deletion in SLITRK1 gene in a boy with Tourette’s syndrome and attention deficit hyperactivity disor- der
(ADHD). The boy’s mother carried the same mutation and suffered from severe TTM. In a 2006 letter to the editor
172 J. Johnson and A.T. El-Alfy
Zuchner et al. [14] proposed that a sequence variation on SLITRKI may play a role in the development of TTM. The research
group sequenced the whole SLITRKI gene of 44 TTM families where at least one member met DSM-IV criteria for TTM.
Researchers discovered two distinct non- synonymous changes in two independent TTM subjects. Both occurred between the
second LRRCT domain and the transmembrane domain of SLITRKI. Zuchner et al. [14] sug- gest that mutations in this position
may be associated with TTM without Tourettes since mutations that were previously observed by Abelson et al. [13] were
located in a different area of the protein. In the study 2192 non-TTM Caucasian controls were screened for this variation and
none were found. Researchers concluded that these sequence variations are sig- nificantly associated with the TTM phenotype.
The other gene implicated in TTM is the HOXB8 gene. Animal studies conducted by Greer and Capecchi reported that
variations in the HOXB8 gene of mice result in excessive grooming that leads to bald sports and skin lesions. They sug- gest a
link between this behavior and the behavior seen in TTM [15]. Many brain areas are involved in initiating a cas- cade of signals
that lead to movements seen in grooming ses- sions. These brain regions include the brainstem and striatum. Excessive grooming
has been observed in OCD and TTM but influential genes in these two disorders have not been elucidated. Greer et al. point out
that mice that are homozy- gous for a loss-of-function mutation in HOXB8 show excessive grooming behavior. The hox genes
are responsible for embry- onic development, hair formation in adult mice, and matura- tion of breast tissue in pregnant females.
The HOXB8 homozygous mutant mice not only demonstrate excessive self-grooming behavior but also excessively groom
control cage mates [15]. Researchers videotaped individual mice from 7 littermate pairs of one wild and one mutant for a 24-h
period in order to see under what conditions the HOXB8 mutants removed their hair. Each mouse was scored for eating, drink-
ing, sleeping and grooming. All aspects were similar in wild type and mutants except for grooming behaviors which showed that
grooming time was doubled in the mutants com- pared to the wild type. The mutants also initiated grooming more frequently
than controls. The researchers point out that the mutant mice groomed all parts of their body which is dif- ferent from TTM
where sufferers focus their pulling on specific areas of the body such as the scalp, eyebrows/lashes, and pubic area. Mutant mice
also spent about one hour less time sleeping than controls as this hour was devoted to grooming [15]. When mutants and wild
type mice were housed together, ‘‘the wild type showed large bald areas on their back and tops of their heads’’. Following video
analysis, it was obvious that the wild type mice were being groomed by the mutants.
Greer and Capecchi [15] conducted a transgenerational study in which they backcrossed F1 generation HOXB8 mutants for 5
generations. The grooming behavior was seen in all homomutants using the home cage and misting- induced grooming assay.
The mutants showed a 2-fold increase in grooming behavior during the induced-grooming assay compared to controls. Hair
removal and skin lesions were visually observed in the mutants as well. Using an RT- PCR assay, researchers showed the
presence of the HOXB8 gene in the adult mouse CNS. Expression was found in the olfactory bulb, basal ganglia, hippocampus,
cortex, cerebellum and the brainstem of the wild type adult.
 It is interesting to note that HOXB8 gene is expressed in the ‘‘OCD circuit’’ which includes the orbitofrontal cortex, the
anterior cingulate cortex and the caudate nucleus. Abnormal metabolic activity is seen in OCD patients within the cells of this
circuit [24]. Overall, Greer et al. state that the excessive grooming behavior observed in mice without HOXB8 function is very
similar to that seen in TTM. They argue that due to the expression pattern of HOXB8 in the CNS and the behavior analysis, TTM
should be classified as an OC-spectrum disorder. Based on the information presented, they believe TTM may be caused by
‘‘misregulation of an innate autogrooming behavior that results in excessive repetition of this behavior’’. Further studies are
needed to determine whether human TTM patients show the mutations reported in the HOXB8 gene [15].
Our current understanding of the neurobiology of TTM is rather incomplete. Despite the fact that most available studies have
focused on neuroimaging, the exact neural circuitry involved in the disorder is not entirely delineated. The overlap between TTM
and other impulsive–compulsive disorders should be further investigated through examining the neurocir- cuits associated with
impulsive and compulsive behavior. Such studies might help identify various subtypes of TTM as they relate to impulse or
compulsive disorders. Additional imaging studies are needed that include unaffected family members of TTM patients. Coupled
to imaging studies, future research should include investigation of receptor distribution and bind- ing in TTM patients as
compared to controls. Serotonin, nora- drenergic, dopaminergic, glutamatergic, and other receptors involved in effective
processing, impulsivity, and compulsion could be examined for abnormal binding using radioligand PET. Additional studies are
needed to examine the role of glu- tamatergic dysfunction in animal models of TTM as well as in TTM patients, especially that
recent data show that abnormal- ities in glutamatergic function might play a role in OCD patho- genesis. Furthermore, the role of
biological and environmental risk factors in the pathogenesis of TTM needs to be studied.
Animal models of trichotillomania
Animal models are important for studying the pathology of various human diseases and disorders [25]. They are valuable tools to
systematically study innumerable disorders as well to investigate potential treatments in a preclinical setting. However, there are
a few limitations associated with develop- ing an animal model, including the fact that most disorders do not develop
spontaneously in the animal being studied and must be induced [25]. However, there are certain behaviors that do develop
spontaneously in confined animals that can be used to mimic human disorders. The following represent examples of each type of
animal model that can be used in studying TTM in experimental animals.
Garner et al. [26] proposed the barbering mouse model as an experimental model to investigate treatment efficacy for TTM.
Barbering is a spontaneous abnormal behavior that commonly develops in caged animals. Researchers believe that because
barbering is an abnormal behavior seen in laboratory mice, and because it occurs spontaneously, such model would be sufficient
to mimic TTM. Results showed that the demogra- phy is similar to TTM (age and gender). It also showed similar
phenomenology (pulling from scalp, around the eyes, and gen- itals) and etiology [26].
Trichotillomania clinical studies and neurobiology review 173
Greer and Capecchi [15] demonstrated that HOXB8 homozygous mutant mice show an increase in grooming behaviors.
These mice display excessive hair removal and increased amount of time spent grooming compared with wild type mice. They
also initiate grooming behaviors more often than controls, and groom their wild type cage mates. Greer and Capecchi [15]
suggest that TTM may occur due to a mis- regulation of a natural autogrooming behavior that results in the excessive repetition
of this behavior that is characteristic of the disorder.
Both animal models show similar characteristics to that of TTM. Either one can be a useful model when trying to deter- mine
the efficacy of treatments for TTM. However, further studies of these models with regard to neurobiology, imaging changes in
brain structure and function, and correlation to changes in TTM patients are warranted in order to validate these models.
Establishing a reliable experimental model of TTM will certainly provide a valuable tool for evaluating pre- clinical
pharmacotherapeutic options for TTM patients.
Commonly used rating scales
Assessment of TTM is a challenging task, as it requires inte- grating information from multiple sources, as well as the fact that it
might heavily rely on patient self-assessment, which can be challenging, particularly in children. Initial diagnosis of the disorder
certainly depends heavily on accurate assess- ment. Several assessment scales have been developed over the past decade. These
assessments include symptoms’ presenta- tion, severity, functional impairment, as well as comorbidity. The following section
summarizes a few of the commonly used clinical scales for the assessment of TTM.
NIMH trichotillomania questionnaire
This questionnaire consists of 2 scales, the NIMH Trichotillomania Severity Scale (NIMH-TSS) and the NIMH Trichotillomania
Impairment Scale (NIMH-TIS). These scales stemmed from the Yale-Brown Obsessive Compulsive scale (Y-BOC scale).
NIMH-TSS contains five questions regarding the average time the patient spent pulling, time spent pulling on previous day,
ability to resist the urge to pull, resulting dis- tress, and daily interference. The scoring range is from 0 to 25 and higher scores
indicate greater severity. The NIMH-TIS classifies the level of impairment from no impairment to severe impairment using a 10-
point scale. This scale takes into account level of embarrassment as well as interference of daily activities caused by noticeable
hair loss. Again, a higher score indicates greater impairment [27].
Clinical Global Impression (CGI) scale
The CGI is a tool used in psychiatry that has the clinician rate, their current patient’s illness severity, improvement, and ther-
apeutic response based on past experiences with patients who also had the disease/disorder. The severity portion is rated on a 7-
point scale with higher points corresponding to the most severely ill (CGI-S). The improvement portion (CGI-I) is also rated on a
7-point scale with higher numbers indicating that the patient is very much improved. The therapeutic
response is rated based on only drug effect. This takes into account both the level of symptom resolution and impairment due to
side effects [28].
Massachusetts General Hospital-Hair Pulling Scale (MGH- HPS)
This is a self-report scale that measures the urge to pull, actual hair-pulling, and the consequences of hair-pulling. It is rated on a
scale from 0 to 4 with higher numbers corresponding to negative outcomes. The section regarding the urge to pull takes into
account the frequency and intensity of the urges, and the ability to control the urges. The second section, which rates the actual
pulling on a 0–4 scale, takes into consideration how often the patient pulled their hair, the frequency of resisting the urge, and
how often the patient was able to control the hair-pulling. For the final section regarding the consequences of hair-pulling, the
patient is asked how uncomfortable or dis- tressed the hair-pulling made them feel [29].
Milwaukee Inventory for Styles of Trichotillomania-Adult Version (MIST-A)
This scale focuses on separating subtypes into 2 distinct classes, automatic and focused. ‘‘Automatic’’ pulling refers to a patient
who is not aware that they are pulling out their hair while ‘‘focused’’ pulling refers to a patient who is inten- tionally pulling out
their hair. The scale is comprised of 15 statements divided into 10 regarding focused pulling and 5 regarding automatic pulling.
Responses to these statements will help classify patients into 1 of the 2 subtypes [30].
Psychiatric Inventory Trichotillomania Scale (PITS)
The PITS is a tool that is administered by a physician that rates the symptoms of hair pulling during the previous week. It is a 6-
item scale and each item is rated from 0 to 7 with higher numbers corresponding to greater severity. Items being assessed in this
scale include the number of hair pulling sites, time spent pulling and thinking about pulling, resistance to urges, distress, and
interference with daily activities [31].
Hamilton Anxiety Rating Scale (HAM-A)
The HAM-A is a clinician-rated scale that measures the degree of anxiety. It consists of 14 items, each being scored from 0 to 4
with 4 denoting severe. Each item is a phrase about the patient’s feelings followed by a list of symptoms. Total score ranges from
0 to 56 with higher numbers indicating very severe anxiety [32].
The availability of multiple TTM-specific rating scales has been crucial in order to properly assess individuals with the
disorder. These scales have been instrumental to clinical trials as they provide an objective assessment of the efficacy of the
proposed therapy and patients’ response to treatment. However, currently available assessment tools do suffer from some
shortcomings. Physician-rated scales are liable to inter- rater variability. While self-reported instruments are crucial, particularly
in the initial baseline assessment of symptoms, many TTM patients lack awareness of hair pulling. In
174 J. Johnson and A.T. El-Alfy
addition, self-monitoring may induce reactivity responses in the patients. Advancement in digital photography might help
researchers and contribute to future accurate quantification of hair density in TTM patients.
Clinical studies/cases for pharmacotherapeutic treatment of TTM
So far the FDA has not approved any pharmacological treat- ment for TTM. Cognitive behavioral therapy (CBT) and habit
reversal therapy (HRT) proved to be effective therapeutic interventions in many cases of TTM. While behavioral thera- peutic
approaches of TTM are not the focus of this review, it is important to note that several randomized controlled trials have reported
behavioral therapy to be effective for the man- agement of TTM patients. On the other hand, available litera- ture regarding
pharmacotherapy of TTM reports equivocal outcomes. Overall, most research studies are comprised of small case reports, small
size trials, and with heavy emphasis on behavioral therapy. Studies that explored pharmacological treatment of TTM have
spanned a variety of drug classes, ranging from antidepressants, antipsychotics, to CNS stimu- lants, and others. The next few
paragraphs summarize the cur- rent literature for TTM pharmacotherapy.
CNS stimulants
Very few clinical studies have focused on CNS stimulants as possible treatment options for TTM. Two studies have sug- gested
that the symptom often seen in TTM patients, the irre- sistible urge to pull out one’s hair is indicative of dysfunction of the
inhibitory neuronal circuits [33,34]. One study reported that TTM patients (n =17) showed statistically significant impaired
inhibitory control when compared to non-TTM patients (n = 20) [32]. Aron et al. [35] correlated the disrup- tion in stop signal,
which is observed in cases of TTM, to a dysfunction in the right inferior frontal gyrus, which causes an increase in stop signal
response. Chamberlain et al. [36] tested the response inhibition of atomoxetine (selective nore- pinephrine reuptake inhibitor) and
citalopram (SSRI) on the norepinephrine and serotonin systems, respectively. The goal of this experiment was to define the
contribution of the sero- tonin and norepinephrine systems to response inhibition and probabilistic learning. Researchers reported
that inhibition of serotonin reuptake, by way of citalopram, had no effect on response inhibition while norepinephrine reuptake
inhibition improved response inhibition in healthy volunteers. Due to these observations, researchers have implicated nore-
pinephrine and inhibitory system dysfunction in the patho- physiology of TTM with the prospect of utilizing CNS stimulants that
up-regulate NE system to manage symptoms of TTM [37]. One such study examined the effects of moda- finil on motor
inhibitory control in TTM [37]. Researchers believed that due to modafinil’s possible effects on nore- pinephrine transmission,
this medication might improve impaired inhibitory control seen in TTM patients. In this 2- week crossover double-blind,
placebo-controlled study, mod- afinil did not show any significant improvement effects on inhibitory control or cognition
enhancement [37]. Similarly, Golubchik et al. [38] performed a study to assess the efficacy and tolerability of methylphenidate in
the treatment of TTM
(with comorbid ADHD) in children and adolescents. No sig- nificant improvement in the severity of TTM was observed. A case
report involving a 30 year-old white female with an 11- year history of TTM that received fenfluramine 20mg showed a drastic
decrease in the urge to pull her hair [39]. It is obvious that there is limited literature regarding the use of CNS stimulants in the
treatment of trichotillomania making it difficult to conclude whether they offer any benefit in the management of the disorder.
More controlled trial studies are certainly needed.
Antiepileptic drugs
Due to TTM being classified by DSM-IV as an impulse control disorder, it is thought that mood stabilizers may be efficacious in
its treatment [40]. The effectiveness of topiramate, an antiepileptic drug that Blocks neuronal voltage-dependent sodium
channels, enhances GABA(A) activity, antagonizes AMPA/kainate glutamate receptors, and weakly inhibits car- bonic anhydrase
enzyme, and oxcarbazepine (that primarily acts by blocking voltage-sensitive sodium channels) might be attributed to the
inhibition of the glutamatergic pathway, that is implicated in compulsive and repetitive behaviors. One of the mechanisms of
actions of valproic acid is the modulation of the GABA system, which is responsible for ‘‘calming’’ the nerves down.
Topiramate has been used in the treatment of other impulse control disorders including binge-eating, skin- picking, pathological
gambling, and kleptomania. However, other recent studies have shown that anticonvulsants are inef- fective in treating impulse
control disorders [41,42]. A case report of an obese patient with binge eating disorder and comorbid TTM was treated with
oxcarbazepine 1200 mg/day. Complete cessation of TTM symptoms was seen after 6months of treatment. A follow-up visit after
9months showed no relapse in hair-pulling and more stable mood [43]. Another case report of a 9 year-old African American girl,
with several comorbid psychiatric disorders, experienced a dramatic reduction of TTM symptoms after an increase in her valproic
acid medication. Valproic acid acts primarily by blockade of voltage-gated Na+ channels and by increasing availability of
gamma-aminobutyric acid (GABA) [44]. The patient was already treated with valproic acid for seizures. When the dose of
valproic acid was increased to control the seizure attacks, it was noted that the urge to pull hair signifi- cantly decreased. Lochner
et al. [40] conducted an open- label, flexible dose study that assessed the efficacy of topira- mate in 14 adults with TTM.
Although topiramate led to a reduction in hair-pulling as the primary outcome measure, there was no statistical significance.
Due to the lack of evidence-based support, it is hard to decide whether antiepileptics are useful in the treatment of TTM. It is
also apparent that the randomized control trials that are available all suffer from a small sample size.
Opioid antagonists
Opioid antagonists are used clinically in the treatment of etha- nol dependence, pathological gambling, and adult kleptoma- nia
[45]. These disorders were classified in DSM-IV as impulse control disorders, along with trichotillomania. Currently,
trichotillomania (hair-pulling disorder) is classified
Trichotillomania clinical studies and neurobiology review 175
under obsessive–compulsive and related disorders along with hoarding, excoriation (skin-picking) disorder, substance-/
medication-induced obsessive–compulsive and related disor- der, and obsessive–compulsive and related disorder due to another
medical condition. Gambling is listed under substance related and addictive disorders and kleptomania is classified under
disruptive, impulse-control, and conduct disorders. The main characteristic observed in TTM patients is hair- pulling; despite the
association of hair-pulling with detrimental effects, including pain, the patient typically disregards these consequences [45].
These observations led researchers to spec- ulate that opioid system dysfunction may be implicated in TTM.
A 10-month long pilot study of 14 children with TTM eval- uated the efficacy of the opioid receptor antagonist, naltrexone on
TTM. Patients showed a statistically significant reduction in CGI-S, hair-pulling, frequency and urge intensity of hair- pulling
[46]. On the other hand, Grant et al. investigated the efficacy of naltrexone in a double-blind placebo controlled trial with 51
TTM patients randomized to naltrexone or placebo. The study showed no difference between naltrexone and pla- cebo in hair
pulling frequency, but significant improvement of cognitive flexibility was observed [46].
Since there are only 2 studies that have tested the efficacy of the opioid antagonist, naltrexone, with obvious variable out-
comes, there is a need for more studies to provide a more con- sistent result. Since both studies showed different results it is
difficult to draw a conclusion about whether naltrexone should be used for the treatment of TTM.
Glutamate modulators
Glutamate is the main excitatory neurotransmitter in the CNS, and excessive amounts of glutamate are known to cause neu- ronal
damage. Since glutamatergic dysfunction has been seen in patients with OCD, a disorder that may be linked to TTM, researchers
believe that using glutamate modulators, such as N-acetylcysteine (NAC), may help restore glutamate concentrations in the brain
to a lower level [22]. NAC is an antioxidant most commonly known for its hepato-protective effects. NAC is metabolized into
cysteine, a substrate for the cysteine-glutamate anti-porter that allows for the uptake of cysteine. The uptake of cysteine causes
the reversal transport of glutamate into the extracellular space. This in turn stimu- lates inhibitory metabotropic glutamate
receptors reducing the synaptic release of glutamate [22].
Following a case report of using NAC in a TTM patient, researchers conducted a 12-week, double-blind, placebo- controlled
trial in order to determine the efficacy and tolerabil- ity of NAC in adult patients with TTM [22]. Patients in the NAC group
showed statistically significant improvement for hair pulling [22]. However, more studies are needed to deter- mine the efficacy
of N-acetylcysteine in the treatment of TTM. Future studies should include a large sample size and a long-term study interval.
Bloch et al. [23] conducted a double-blind placebo con- trolled study that investigated the efficacy of NAC as an add-on
treatment for TTM in a pediatric population. A change in severity of TTM was the primary outcome of the study, and the results
revealed no significant difference between NAC and placebo-treated patients.
Table 1 Summary of clinical studies/case reports of potential pharmacotherapy of trichotillomania.
Study Agent/drug Subjects Dosage and treatment duration Assessment measure Main outcome Side effects
Effects of acute modafinil on cognition in trichotillomania [37]
Modafinil (CNS stimulant)
18 patients (14 female and 4 male), with a mean age of 33.4
200 mg for the 1st week and placebo the second week
Inhibitory control and cognitive enhancement
No significant improvement
Not stated
Methylphenidate treatment in pediatric patients with attention-deficit/ hyperactivity disorder and comorbid trichotillomania: a
preliminary report [38]
Methylphenidate (CNS stimulant)
Nine children (6 female and 3 male), aged 6–18 years, were treated with methylphenidate
0.5–0.7 mg/kg for 12 weeks Severity of TTM and
tolerability of treatment
No significant improvement in severity of TTM
Decrease in appetite Headache Excessive preoccupation with one’s hair Abdominal pain Motor tic exacerbation
Fenfluramine and trichotillomania [39]
Fenfluramine (CNS stimulant)
Case report of a 30 year old female received fenfluramine after an 11 year history of TTM. The patient was partially responsive
on fluoxetine and sertraline
Fenfluramine, 20 mg, was added to the daily regimen of sertraline (100 mg) and alprazolam (1 mg). Patient continued on
fenfluramine alone for remission
Urge to pull hair Significant decrease in
urge to pull hair
Not stated
Oxcarbazepine for the treatment of trichotillomania [43]
Oxcarbazepine (anticonvulsant, mood stabilizer)
Case report of a 43-year-old woman with binge eating disorder and comorbid TTM
Flexible dosing of oxcarbazepine up to 1200 mg/day
Hair pulling and eating behavior
The patient reported improvement in hair pulling and eating behavior after 6 months of treatment, and with no relapse after 9
months
Sleepiness Confusion Asthenia
Trichotillomania: a case response to valproic acid [44]
Valproic acid (anticonvulsant, mood stabilizer)
Case report of a 9 year-old African American girl, with several comorbid psychiatric disorders
Patient was already on valproic acid for seizures. Dosing regimen was increased with trough levels range between 115 and 125
mg/100 mL
TTM symptoms and urge to pull hair
Patient reported a significant decrease in urge to pull hair and an increase in hair growth
Not stated
Topiramate in the treatment of trichotillomania; an open-label pilot study [40]
14 adults (13 female and 1 male), aged 19–43 years, for the treatment of TTM
A 16-week open-label, flexible dose study; the initial dose was 25 mg every evening for 7 days. On day 8, the dose was increased
to 50 mg and increased again to 75 mg on day 15. Dose increases of 25 mg were allowed at the beginning of weeks 4–7 and a
final increase in weeks 8–12 to a maximum of 250 mg
TTM severity by the MGH-HPS
A non-significant reduction in TTM severity
Paraesthesia Speech/language difficulty Increased anxiety Weight loss Nausea Headache/migraine Insomnia Myalgia Depressed
mood Double/blurry vision Dry mouth
A An open-label pilot
Naltrexone (opioid
Nine (9) girls and
Naltrexone started at
CGI-S, hair pulling,
statistically

one experienced study of naltrexone in

antagonist)
5 boys (mean age of 9)
25 mg/day and was
frequency, and
s
ignificant reduction in childhood-onset
with TTM as primary
increased to a
intensity of hair pulling
a
ll TTM measured trichotillomania [45]
diagnosis were included
maximum of 100 mg
parameters was observed in a 10 month pilot
study.
(based on symptoms) Only those receiving
after 1 week naltrexone as monotherapy were included. Exclusion criteria were those receiving
concomitant CBT or psychotherapy and those with other diagnoses
The opiate antagonist, naltrexone, in the treatment of trichotillomania: results of a double-blind, placebo-controlled study [46]
Mild sedation No significant effect on liver function
N-Acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study [22]
Naltrexone
Fifty-one (51) TTM patients,
Patients were given
TTM severity using
No significant (Opioid
antagonist)
males and females,
naltrexone over an
MGH-HPS and
effect on hair pulling mean age of 32.7
8 week period. Dose
cognitive function
Naltrexone group started at 50 mg/d, and
using the
showed significant increased to 10 mg/d
intradimensional
improvement of after 2 weeks, then to
/extradimensional
cognitive flexibility 150 mg/d after 4 weeks
differences between c
Nausea Diarrhea Cough
N-Acetylcysteine as an add-on treatment for TTM in children and adolescents [23]
N-Acetylcysteine
Fifty (50) adults
Patients were given
TTM severity by
Significant decrease
(NAC) glutamate
(45 women and 5 men),
NAC 1200 mg/d, or
MGH-HPS, CGI,
in hair pulling
modulator antioxidant
aged 18–65 years old
placebo, for 6 weeks.
PITS psychosocial
(MGH-HPS and PITS) At week 6, the dose was
functioning, increased to 2400 mg/d
depression, and anxiety for the next 6 weeks
N-Acetylcysteine (NAC)
Thirty-nine (39)
NAC was titrated over
TTM severity
No significant
N
ausea, diarrhea, fatigue, Glutamate modulator
children/adolescents
the course of 4 weeks to
MGH-HPS, TSC-C, P),
improvement
 i
nsomnia, rash, depression, Antioxidant
between the ages of 8 and
a maximum dose of
NIMH-TSS, MIST-C,
in hair pulling in
and difficulty in
swallowing 17 years old who had
2400 mg. The study
CGI (Clinical Global
response to NAC
the pills were reported
by a primary diagnosis of TTM,
continued for 12 weeks
Impression) depression,
treatment
both NAC and
placebo but no other psychiatric,
anxiety, and adverse effects
groups. Nausea was
more mental, developmental disorder,
significantly reported
in asthma, or substance use
the placebo compared
to the disorder All participants
NAC group were
receiving pharmaco- and psychotherapy that started >3 months prior to the trail and continued the therapy during the trial
(continued on next page)
Table 1 (continued)
Study Agent/drug Subjects Dosage and treatment duration Assessment measure Main outcome Side effects
Dronabinol, a cannabinoid agonist, reduces hair pulling in TTM [47]
Dronabinol Synthetic D
14 patients (all female), aged 18–65, were started on dronabinol
Dronabinol administered at 2.5 mg/d for 3 weeks, and at week 3, the dose was increased to 5 mg/d for 3 weeks, and then
increased to 10 mg/d at week 6 for 3 weeks, and to 15 mg/d at week 9 for 3 weeks
TTM severity by MGH-HPS and CGI scale neurocognitive tests
Statistical significant improvement in TTM score, with no significant effect on cognitive functions
No significant adverse effects on cognition reported
Escitalopram treatment of trichotillomania [48]
9
-Tetrahydrocannabinol
Escitalopram Antidepressant; SSRI
20 women, aged 18–60
Patients started on escitalopram 10 mg/day for 4 weeks, then the dose could be increased to 20 mg/day based on clinical
responsiveness, and at 8 weeks the dose was increased to 30 mg/day
TTM severity by TSS and ITT
Significant decrease in TTM severity
Nausea Insomnia Fatigue Lethargy Sweating Dilated pupils Decreased libido Orgasmic Dysfunction Bruising Skin rash
Use of the selective serotonin reuptake inhibitor citalopram in the treatment of trichotillomania [49]
Citalopram Antidepressant; SSRI
14 patients, not currently receiving a SSRI, 13 female and 1 male, aged 20–45
Citalopram was given initially at 20 mg/day and was increased every 2 weeks, based on clinical response, to a maximum of 60
mg/day
TTM severity by Y-BOCS, NIMH-OCS, and CGI scale depression
Significant reduction in TTM severity and comorbid depression
Headache Diminished sexual desire Sleepiness/sedation Tension Orgasmic dysfunction Decreased salvation Nausea/vomiting
Tremor Weight gain Constipation Weight loss Orthostatic dizziness Palpitations/tachycardia Increased yawning
A long-term, double-blind, placebo-controlled crossover trial of the efficacy of fluoxetine for trichotillomania [50]
Fluoxetine Antidepressant; SSRI
16 patients (14 women and 2 men), aged 20–68
Patients were initially given fluoxetine 20 mg/day that was increased to 80 mg/day over 12 weeks. The study started with a 2-
week placebo washout period, followed by a 12-week treatment period, 5-week washout period, and a 12-week crossover
treatment period
Severity of TTM, severity of hair pulling, urge to pull, days of hair pulling, and daily hair counts
No significant effect of fluoxetine on severity of TTM
Nightmares Insomnia Dizziness Irritability Anxiety Nausea Diarrhea Constipation Anorgasmia Decreased appetite Increased
weight
Frequency Bupropion XL for the
Bupropion Antidepressant;
Case report, 35 year
Bupropion given at
of hair pulling Patient reported

ecreased appetite sustained treatment of

Dopamine,
old with 8-year history
150 mg/day, was
complete cessation

eight loss trichotillomania [51]

norepinephrine-reuptake
of TTM had been treated
increased after 1 week
of hair pulling
after inhibitor
with psychotherapy,
to 300 mg/day,
2 weeks of pharmacotherapy,
and again after
bupropion treatment and hypnosis,
2 weeks to 450 mg/day in addition to
A case of trichotillomania successfully treated with clomipramine [52]
Not stated
Lithium treatment of chronic hair pulling [39]
Clomipramine
Case report, 17-year-old
Patient prescribed
Urge to pull hair Patient reported the
Antidepressant;
girl with TTM initially
clomipramine,
ability to resist
Tricyclic antidepressant
underwent psychotherapy
30 mg/day for 2 weeks
the urge to pull out hair for treatment with no
avail
after 2 weeks of treatment
Increased thirst Weight gain Tremor
Lithium treatment of trichotillomania with comorbid bipolar II disorder [54]
Lithium Antimanic Ten patients Lithium 900–1500 mg
Hair pulling and
Eight patients reported administered for
hair regrowth
decreased hair pulling 2–14 months
and mild-moderate hair growth
Not stated
Lithium treatment of trichotillomania with comorbid bipolar II disorder [54]
Lithium Antimanic A case report of a
Lithium treatment
TTM severity TTM symptoms improved 26-year old woman
was initiated, then
within 4 days. Complete with TTM,
exacerbated
the dose was slowly
cessation of that hair postpartum, bipolar
increased to 900 mg
pulling urge was II disorder, panic disorder,
reported following and cannabis dependence.
7 months treatment She had been previously
with a higher lithium dose prescribed various
medications for treatment including sertraline, paroxetine, risperidone, and quetiapine
Not stated
A randomized, double- blind, placebo- controlled trial of olanzapine in the treatment of trichotillomania [20]
Lithium Antimanic A case report of a
Patient treated
TTM severity and
A significant reduction 27-year old pregnant
with lithium
urgency to pull hair
in TTM score and woman, with TTM and
urgency to pull her hair co-morbid bipolar II
was observed disorder
after 6 weeks of treatment
Olanzapine Antipsychotic Twenty-five (25) patients
Flexible dose olanzapine
TTM severity Olanzapine significantly
Dry mouth (17
women and 8 men),
(2.5–20 mg/d) or placebo.
reduced TTM severity
Fatigue aged 18–
65 years,
Patients were given 2.5 mg/d
as compared to
Increased appetite
randomly assigned
for weeks 0–3, up to 5 mg/d
placebo group
Headache The
primary efficacy
for weeks 4 and 5, up to
Weight gain
measure was the
10 mg d for weeks 6 and 7, CGI-I scale
and up to 20 mg/d for weeks 8–12
(continued on next page)
Table 1 (continued)
Study Agent/drug Subjects Dosage and treatment duration Assessment measure Main outcome Side effects
The potential role of haloperidol in the treatment of trichotillomania [19]
Haloperidol First generation antipsychotic
Nine (9) patients (all women, with an average age of 32.8 years)
Six patients who had a partial response or no response to SSRIs were treated with haloperidol and an SSRI. The three other
patients only received haloperidol. Doses ranged from 0.25 mg/d to 2 mg/d. Four patients received fluoxetine as their SSRI, 1
received paroxetine, and another received fluvoxamine
Researchers used the Structured Clinical Interview for DSM-III-R and a modified Minnesota Trichotillomania Assessment
Inventory to evaluate patients. Response to treatment was based on descriptions of hair pulling, quantity of hair pulled, and
severity of depilation at hair pulling sites
Eight of the nine patients responded to haloperidol with near complete cessation of hair pulling. Two patients discontinued
haloperidol but experienced a relapse in hair pulling
Sedation Increased heart rate Restlessness Constipation
Reversal of trichotillomania with aripiprazole [21]
Aripiprazole Second generation antipsychotic
Case report of a 32-year old woman with a 19-year history of TTM, co-morbidity of major depression and mild/moderate OCD
Aripiprazole started at 15 mg/day, continued till hair pulling cessation
Severity of TTM, cessation of hair pulling, monitor for relapse
The patient reported a reduction of hair pulling by day 10 and complete cessation by day 21. Complete cessation continued for 24
months with no recurrence
Not stated
Resistant trichotillomania and risperidone [54]
Risperidone Second generation antipsychotic
Case report of a 22-year-old woman with antisocial personality disorder and comorbid TTM
Risperidone treatment started and dosage was increased to 4 mg/day
TTM symptoms’ cessation
Patient reported complete cessation of TTM symptoms for 8 months
Not stated
Synthetic D9-Tetrahydrocannabinol (D9-THC)
As previously stated, there has been interest in targeting gluta- matergic dysfunction in the treatment of TTM. D9-THC, a
phytocannabinoid constituting the major active ingredient of cannabis, interacts with the endocannabinoid system (through the
cannabinoid CB1 and CB2 receptors) that serves as a neu- romodulator for a myriad of neurotransmitters, including glu- tamate.
Grant et al. [47] have shown that dronabinol, a synthetic THC, targets the overproduction of glutamate that is implicated in the
symptoms seen in TTM. THC binds to cannabinoid receptors (CB1Rs) inhibiting the release of gluta- mate onto CA1 neurons.
The activation of CB1 receptor has been shown to inhibit glutamate-induced excitotoxicity, and it is believed that in
trichotillomania there is a loss of function in these receptors. Hence, Grant et al. examined the effect of dronabinol in the
management of TTM [47]. In a 12-week open-label study, researchers hypothesized that dronabinol would reduce hair pulling
behavior in TTM patients. Statistically significant improvements were observed for TTM scores. Grant and colleagues also
included neurocogni- tive testing to determine any adverse effects of THC on mem- ory, attention, executive function, and
psychomotor speed. The results showed that there were no significant effects on any of these cognitive factors. Targeting CB1
receptors repre- sents a newer area of research that should be further explored. Based on the results from Grant et al. [47] more
research is needed to elucidate the possible efficacy of the cannabinoid agonist, dronabinol or other analogs, in the treatment of
TTM. Longer duration of the studies is also needed to assess long term effects of these compounds.
Antidepressant agents
The use of antidepressants in the treatment of TTM stems from the belief that TTM is linked to OCD due to the presen- tation of
repetitive symptoms [7]. Some authors believe that TTM should be classified with OCD along with other disor- ders that have
similar behavioral symptoms [7]. In a 12- week, open-label, flexible-dose study, Gadde et al. reported a significant decrease in
the trichotillomania severity in patients treated with the SSRI, escitalopram [48]. A similar study was previously conducted by
Stein et al. [49], whereby a 12-week, open-label trial was performed using the SSRI, citalopram, in TTM patients. The study
reported a significant reduction in TTM severity as well as in comorbid depression. On the other hand, a 31-week, double blind,
placebo-controlled cross- over trial showed no statistically significant effect of fluoxetine on TTM severity [50].
Despite the conflicting results with the SSRI antidepressant trials, a few scattered case studies report positive response of
individual TTM patients to antidepressant therapy. A case report involving a 35-year-old with an 8-year history of TTM had been
treated with psychotherapy, pharmacotherapy, and hypnosis. Previous medication included clomipramine, sertraline, paroxetine,
citalopram, escitalopram, klonopin, aripiprazole, and 4 trials of fluoxetine. Bupropion XL, a dopa- mine and norepinephrine
reuptake inhibitor, was started and within 2 weeks of starting treatment, the patient reported com- plete cessation of hair pulling
[51]. Similarly, a 17-year-old girl with TTM initially underwent psychotherapy for the treatment
Trichotillomania clinical studies and neurobiology review 181
with no avail. She was prescribed clomipramine, a tricyclic antidepressant, and after 2 weeks reported the ability to resist the urge
to pull out her hair [52].
Although antidepressants were once thought to be the first line of choice in treating the TTM, research has shown that
antidepressants do not offer consistent positive results. However, SSRIs might be useful in the management of comor- bid
depression or anxiety symptoms associated with TTM. A recent random effect meta-analysis study conducted by McGuire et al.
[53] examined the efficacy of SSRI therapy in 11 randomized controlled trials. The study reported a moder- ate treatment pooled
effect size of SSRIs. Current research is focused on examining the potential effectiveness of other drug classes with different
mechanisms of action.
Antimanic mood-stabilizing drugs
Since TTM was previously classified as an impulse control dis- order and does not currently have any FDA-approved treat- ment
option, a wide variety of medications are used to attempt to treat it [54]. Among these medications lithium is the most commonly
used antimanic. An early study reported that, in an uncontrolled trial of lithium, 8 out of 10 patients showed decrease in hair
pulling and a tendency for hair regrowth [55]. Sharma and Corpse [54] reported two case reports of effective use of lithium in
TTM patients. A case report of a 26-year-old pregnant woman with TTM had expe- rienced symptom exacerbations postpartum.
Lithium was ini- tiated and within 4 days the patient reported a decrease in the urge to pull out her hair. Another case report of a
27- year-old woman (at 24 week gestation), with bipolar II disor- der and a history of TTM was given lithium and reported a
reduction in the urge to pull hair.
The limited reported studies described above do not pro- vide concrete evidence of the effectiveness of antimanic drugs in
TTM. Additionally, the existence of comorbid bipolar disor- der in these cases suggests that positive findings might be attributed
to the mood stabilizing effects of these agents.
Antipsychotic agents
Although many researchers believe TTM is similar to OCD, others believe the behavior observed in TTM resembles tics seen in
Tourette’s syndrome [19]. Both hair pulling and tics occur unconsciously and do not respond well to SSRIs. Due to the fact that
Tourette’s syndrome responds well to antipsy- chotic medications, researchers believe TTM might too. So far, trials have been
concluded with the antipsychotics olanzapine, haloperidol, and aripiprazole. In a 12-week, double-blind, placebo-controlled trial
researchers tested the efficacy of olan- zapine, a potent antagonist of serotonin, dopamine, histamine, and alpha
1
-adrenergic receptors, in the treatment of TTM. Olanzapine was shown to be significantly superior to the pla- cebo in
reducing TTM severity score [20]. The same research group conducted an open trial of haloperidol in the treatment of TTM.
Haloperidol is a high potency first generation antipsychotic that blocks postsynaptic mesolimbic dopaminer- gic D1 and D2
receptors [19]. Van Ameringen et al. conducted a study on nine TTM patients. Six patients who had a partial response or no
response to SSRIs were treated with haloperi- dol and an SSRI. The three other patients only received
haloperidol. Eight of the nine patients responded to haloperi- dol with near complete cessation of hair pulling. Two patients
eventually discontinued haloperidol and experienced a relapse in hair pulling [19]. Only one case study reported complete ces-
sation of hair-pulling, with no relapse up to 24 months. The case was of a 32-year old woman with a 19-year history of TTM with
co-morbidity of major depression and mild/moder- ate OCD. The patient was administered aripiprazole (a second generation
antipsychotic that serves as a partial agonist at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors) for the
treatment of TTM. The patient reported a reduction of hair pulling by day 10 and complete cessation by day 21. Complete
cessation continued for 24 months with no recurrence [21]. Another case reported a 22-year-old woman with antisocial
personality disorder and comorbid TTM treated with risperidone. Risperidone is another second generation antipsychotic agent
that acts as a selective monoaminergic antagonist with a strong affinity for serotonin Type 2 (5-HT2) receptors and a slightly
weaker affinity for dopamine Type 2 (D2) receptors. A decrease in hair pulling was seen after 4 weeks of treatment. Complete
cessation of TTM symptoms was reported and continued for 8 months fol- lowing increasing the risperidone dose [54]. As
evident, the cur- rently available literature evaluating the use of antipsychotics in TTM is scattered, with a few isolated case
reports and a cou- ple of trials that suffer from small sample size as a major short- coming. As such it is hard to reach any
conclusions regarding the effectiveness of this class of drugs and its potential contri- bution to the therapeutic management of
TTM.
Table 1 summarizes the details and results of the available clinical trials and case reports reviewed. Based on these studies it is
apparent that there is still no consistent treatment option available for TTM. Researchers have explored a variety of drug classes,
with different mechanisms of action in an attempt to provide an effective treatment strategy. From stimulants to anti-depressants
to an opioid antagonist, future studies are warranted, especially that there are several problems associ- ated with many of the
currently available trial studies. A few of these problems are, of course, the scarcity of trials, the small sample sizes,
inconsistencies in inclusion criteria (concurrent psychotherapy and pharmacotherapy), short trial duration, and lack of follow-up
data. Furthermore, as seen in Table 1, many of these pharmacotherapies employed so far are associ- ated with adverse effects that
impede patient’s compliance, especially for long term usage. Based on the limited data at hand, it seems that NAC, dronabinol,
and naltrexone might provide potential treatment options for TTM. However, more clinical trials with large sample sizes are
needed in order to conclusively study their effectiveness. Although previous stud- ies showed statistically significant results, it
remains to be seen whether that would hold true in a larger population.
Conclusions
Trichotillomania (TTM) is a disabling disorder in which indi- viduals have the urge to pull their hairs out. Unfortunately, TTM is
under recognized and there is a lack of research and funding devoted to the disorder. Most of the research of TTM has been
focused on whether it should be considered an OCD subset instead of aiming to explain and treat the dis- order. Our current lack
of understanding of the etiology and
182 J. Johnson and A.T. El-Alfy
pathophysiology of the disorder certainly hinders the efforts for proper treatment, let alone the proper classification of the
disorder. The never ending debate of TTM classification as an impulse versus OCD necessitates further insights into the
neurobiology of the disorder. Future research should focus on utilizing advanced imaging technology, coupled to experi- mental
animal models, for mechanistic investigation of neural circuits involved in the disorder. Additional studies that explore the role of
various neurotransmitter pathways in the etiology and pathophysiology of the disorder are certainly warranted. The serotonergic,
dopaminergic, and glutamatergic pathways are among the top candidates to be investigated, and the role of genes of these
pathways in the pathogenesis of TTM needs to be examined.
So far, behavioral approaches seem to be the first line of therapy for most patients. The use of NAC as a first line phar-
macological treatment, particularly in adult TTM patients is increasing. However, the use of pharmacotherapy, either alone, or as
add-on treatments, needs to be further investi- gated. Currently, the various pharmacological approaches adopted for TTM lack
solid clinical evidence because of unavailability of controlled studies with suitable sample size. In addition, effectiveness seems
to be highly individualized, and might be hindered by the side effect profile associated with these medications. Accordingly,
controlled trials are needed to assess the effectiveness of this approach as well as to compare it with behavioral alternatives.
Finally, it is imperative to bring awareness to TTM and for it to be recognized as a debilitating disorder. Not only do indi-
viduals struggle emotionally but also physically, as they have to endure the embarrassment and shame of hair loss. Those with
TTM often resort to social isolation due to embarrass- ment, and better understanding and awareness of the disorder is certainly
the first step toward helping these patients.
Conflict of Interest
The authors have declared no conflict of interest.
Compliance with Ethics Requirements
This article does not contain any studies with human or animal subjects.
References
[1] Christenson GA, Popkin MK, Mackenzie TB, Realmuto GM. Lithium treatment of chronic hairpulling. J Clin Psychiat
1991;52:116–20. [2] Stein DJ, Grant JE, Franklin ME, Keuthen N, Lochner C, Singer HS, Woods HS. Trichotillomania (hair
pulling disorder), skin picking disorder, and stereotypic movement disorder: toward DSM-V. Depress Anxiety 2010;27(6):611–
26. [3] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC; 2013..
[4] Flessner CA, Conelea CA, Woods DW, Franklin ME, Keuthen NJ, Cashin SE. Styles of pulling in trichotillomania: exploring
differences in symptom severity, phenomenology, and functional impact. Behav Res Ther 2008;46(3):345–57. [5] Du Toit PL,
Van Kradenburg J, Niehaus DJH, Stein DJ. Characteristics and phenomenology of hair-pulling: an exploration of subtypes.
Compr Psychiat 2001;42(3):247–56.
[6] Mackenzie TB, Christenson GA, Lebow AS, Mitchell JE. Identification of cues associated with compulsive, and hair- pulling
symptoms. J Behav Ther Exp Psychiat 1995;26(1):9–16. [7] Lochner C, Seedat S, du Toit PL, Nel DG, Niehaus DJH, Sandler R,
Stein DJ. Obsessive–compulsive disorder and trichotillomania: a phenomenological comparison. BMC Psychiat 2005;13(5):2. [8]
Christenson GA, Mackenzie TB, Mitchelle JE. Characteristics of 60 adult chronic hair pullers. Am J Psychiat 1991;138(3):365–
70. [9] Nikolaus S, Antke C, Beu M, Muller HW. Cortical GABA, striatal dopamine and midbrain serotonin as the key players in
compulsive and anxiety disorders: results form in vivo imaging studies. Rev Neurosci 2010;21(2):119–39. [10] Grachev ID.
MRI-based morphometric topographic parcellation of human neocortex in trichotillomania. Psychiat Clin Neurosci
1997;51(5):315–21. [11] Chamberlain SR, Menzies LA, Fineberg NA, Del Campo N, Suckling J, Craig K, Muller U, Robbins
TW, Bullmore ET, Sahakian BJ. Grey matter abnormalities in trichotillomania: morphometric magnetic resonance imaging study.
Br J Psychiat: J Ment Sci 2008;193(3):216–21. [12] Odlaug BL, Chamberlain SR, Derbyshire KL, Leppink EW, Grant JE.
Impaired response inhibition and excess cortical thickness as candidate endophenotypes for trichotillomania. J Psychiat Res
2014;59:167–73. [13] Abelson JF, Kwan KY, Roak BJO, Baek DY, Stillman AA, Morgan TM, Matthews CA, Pauls DL, Rasin
MR, Gunel M, Davis NR, Ercan-Sencicek AG, Guez DH, Apertus JA, Leckman JF, Dure 4th LS, Kurlan R, Singer HS, Gilber
DL, Farhi A, Louvi A, Lifrton RP, Sestan W, State MW. Sequence variants in SLITRK1 are associated with Tourette’s
syndrome. Science 2005;310(5746):317–20. [14] Zuchner S, Cuccaro ML, Tran-Viet KN, Cope H, Krishnan RR, Pericak-Vance
MA, Wright HH, Ashley-Koch A. SLITRK1 mutations in trichotillomania. Mol Psychiat 2006;11(10):887–9. [15] Greer JM,
Capecchi MR. Hoxb8 is required for normal
grooming behavior in mice. Neuron 2002;33(1):23–34. [16] Aldridge JW, Berridge KC, Herman M, Zimmer L. Research
report neuronal coding of serial order: syntax of grooming in the neostriatum. Psychol Sci 1993;4(6):391–5. [17] Poulos CX,
Parker JL, Le AD. Dexfenfluramine and 8-OH- DPAT modulate impulsivity in a delay-of-reward paradigm: implications for a
correspondance with alcohol consumption. Behav Pharmacol 1996;7(4):395–9. [18] Mobini S, Chiang Rj, Al-Ruwaitea AS, Ho
MY, Bradshaw CM, Szabadi E. Effect of central 5-hydroxytryptamine depletion on inter-temporal choice: a quantitative analysis.
Psychopharmacology 2000;149(3):313–8. [19] Van Ameringen M, Mancini C, Oakman JM, Farvolden P. The potential role of
haloperidol in treatment of trichotillomania. J Affect Disorders 1998;56(2–3):219–26. [20] Van Ameringen M, Mancini C,
Patterson B, Bennett M, Oakman J. A randomized, double-blind, placebo-controlled trial of olanzapine in the treatment of
trichotillomania. J Clin Psychiat 2010;71(10):1336–43. [21] Jefferys D, Burrows G. Reversal of trichotillomania with
aripiprazole. Depress Anxiety 2008;25(6):E37–40. [22] Grant JE, Odlaug BL, Kim SW. N-acetylcysteine, a glutamate
modulator, in the treatment of trichotillomania: a double- blind, placebo-controlled study. Arch Gen Psychiat 2009;66: 756–63.
[23] Bloch MH, Panza KE, Grant JE, Pittenger C, Leckman JF. N- Acetylcysteine in the treatment of pediatric trichotillomania: a
randomized, double-blind, placebo-controlled add- on trial. J Am Acad Child Adolesc Psychiat 2013;52(3):231–40. [24] Graybiel
AM, Rauch SL. Toward a neurobiology of obsessive–
compulsive disorder. Neuron 2000;28(2):343–7.
Trichotillomania clinical studies and neurobiology review 183
[25] Geyer MA, Markou A. Animal models of psychiatric disorders. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: the
fourth generation of progress. New York: Raven Press, Ltd; 2000. [26] Garner JP, Weisker SM, Dufour B, Mench JA. Barbering
(fur and whisker trimming) by laboratory mice as a model of human trichotillomania and obsessive–compulsive spectrum
disorders. Comp Med 2004;54(2):216–24. [27] Swedo SE, Leonard HL, Rapoport JL, Lenane MC, Goldberger EL, Cheslow DL.
A double-blind comparison of clomipramine and desipramine in the treatment of trichotillomania (hair pulling). N Engl J Med
1998;321(8):497–501. [28] Guy W. Clinical global impression (CGI). ECDEU Assess
Manual Psychopharmacol 2003;1:125–6. [29] Keuthen NJ, O’Sullivan RL, Ricciardi JN, Shera D, Savage CR, Borgmann
AS, Jenike MA, Baer L. The Massachusetts general hospital (MGH) hair-pulling Scale: 1. Development and factor analyses.
Psychother Psychosomat 1995;64(3–4):141–5. [30] Flessner CA, Woods DW, Franklin ME, Cashin SE, Keuthen NJ. The
Milwaukee inventory for subtypes of trichotillomania- adult version (MIST-A): development of an instrument for the assessment
of ‘‘focused’’ and ‘‘automatic’’ hair pulling. J Psychopathol Behav Assess 2007;30(1):20–30. [31] Winchel RM, Jones JS,
Molcho A, Parsons B, Stanley B, Stanley M. The Psychiatric Institute Trichotillomania Scale (PITS). Psychopharmacol Bull
1992;28(4):463–76. [32] Hamilton M. The assessment of anxiety states by rating. Br J
Med Psychol 1959;32(1):50–5. [33] Chamberlain SR, Fineberg NA, Blackwell AD, Robbins TW, Sahakian BJ. Motor
inhibition and cognitive flexibility in obsessive–compulsive disorder and trichotillomania. Am J Psychiat 2006;163(7):1282–4.
[34] Stein DJ, Chamberlain SR, Fineberg N. An A-B-C model of habit disorders: hair-pulling, skin-picking, and other stereotypic
conditions. CNS Spectr 2006;11(11):824–7. [35] Aron AR, Fletcher PC, Bullmore ET, Sahakian BJ, Robbins TW. Stop-signal
inhibition disrupted by damage to right inferior frontal gyrus in humans. Nat Neurosci 2003;6(2):115–6. [36] Chamberlain SR,
Mu ̈ller U, Blackwell AD, Clark L, Robbins TW, Sahakian BJ. Neurochemical modulation of response inhibition and
probabilistic learning in humans. Science 2006;311(5762):861–3. [37] Chamberlain SR, Grant JE, Costa A, Mu ̈ller U, Sahakian
BJ. Effects of acute modafinil on cognition in trichotillomania. Psychopharmacology 2010;212:597–601. [38] Golubchik P,
Sever J, Weizman A, Zalsman G. Methylphenidate treatment in pediatric patients with attention-deficit/hyperactivity disorder
and comorbid trichotillomania: a preliminary report. Clin Neuropharmacol 2011;34(3):108–10. [39] Mahr G. Fenfluramine and
trichotillomania. Psychosomatics
1991;34(3):284. [40] Lochner C, Seedat S, Niehaus DJH, Stein DJ. Topiramate in the treatment of trichotillomania: an open-
label pilot study. Int Clin Psychopharmacol 2006;21(5):255–9. [41] Berlin HA, Braun A, Simeon D, Koran LM, Potenza MN,
McElroy SL, Fong T, Pallanti S, Hollander E. A double-blind, placebo-controlled trial of topiramate for pathological gambling.
World J Biol Psychiat 2013;14(2):121–8. [42] Grant JE, Odlaug BL, Chamberlain SR, Kim SW. A double- blind, placebo-
controlled trial of lamotrigine for pathological skin picking: treatment efficacy and neurocognitive predictors of response. J Clin
Psychopharmacol 2010;30(4):396–403. [43] Leombruni P, Gastaldi F. Oxcarbazepine for the treatment of
trichotillomania. Clin Neuropharmacol 2010;33(2):107–8. [44] Adewuya EC, Zinser W, Thomas C. Trichotillomania: a case
of response to valproic acid. J Child Adolesc Psychopharmacol 2008;18(5):533–6.
[45] De Sousa A. An open-label pilot study of naltrexone in childhood-onset trichotillomania. J Child Adolesc Psychopharmacol
2008;18(1):30–3. [46] Grant JE, Odlaug BL, Schreiber LRN, Kim SW. The opiate antagonist, naltrexone, in the treatment of
trichotillomania: results of a double-blind, placebo-controlled study. J Clin Psychopharmacol 2014;34(1):134–8. [47] Grant JE,
Odlaug BL, Chamberlain SR, Kim SW. Dronabinol, a cannabinoid agonist, reduces hair pulling in trichotillomania: a pilot study.
Psychopharmacology 2011;218(3):493–502. [48] Gadde KM, Ryan Wagner H, Connor KM, Foust MS. Escitalopram treatment
of trichotillomania. Int Clin Psychopharmacol 2007;22(1):39–42. [49] Stein DJ, Bouwer C, Maud CM. Use of the selective
serotonin reuptake inhibitor citalopram in treatment of trichotillomania. Eur Arch Psychiat Clin Neurosci 1997;247(4):234–6.
[50] Streichenwein SM, Thornby JI. A long-term, double-blind, placebo-controlled crossover trial of the efficacy of fluoxetine
for trichotillomania. Am J Psychiat 1995;152(8):1192–6.
184 J. Johnson and A.T. El-Alfy
[51] Klipstein K, Berman L. Bupropion XL for the sustained treatment of trichotillomania. J Clin Psychopharmacol
2012;32(2):298–9. [52] Takei A. Letter to the Editor A case of trichotillomania successfully treated with clomipramine. Psychiat
Clin Neurosci 2000;54(4):513. [53] McGuire JF, Ung D, Selles RR, rahman O, Lewin AB, Murphy TK, Storch EA. Treating
trichotillomania: a meta analysis of treatment effects and moderators for behavior therapy and serotonin reuptake inhibitors. J
Psychiat Res 2014;58:76–83. [54] Sharma V, Corpse C. Lithium treatment of trichotillomania with comorbid bipolar II disorder.
Arch Women’s Ment Health 2008;11(4):305–6. [55] Christenson GA, Popkin MK, Mackenzie TB, Realmuto GM. Lithium
treatment of chronic hair pulling. J Clin Psychiat 1991;52(3):116–20.