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Pharmacotherapy for trichotillomania

  1. Rachel Rothbart1,
  2. Taryn Amos2,
  3. Nandi Siegfried2,
  4. Jonathan C Ipser2,
  5. Naomi Fineberg3,
  6. Samuel R Chamberlain4,
  7. Dan J Stein2,*

Editorial Group: Cochrane Depression, Anxiety and Neurosis Group

Published Online: 8 NOV 2013

Assessed as up-to-date: 31 JUL 2013

DOI: 10.1002/14651858.CD007662.pub2


How to Cite

Rothbart R, Amos T, Siegfried N, Ipser JC, Fineberg N, Chamberlain SR, Stein DJ. Pharmacotherapy for trichotillomania. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD007662. DOI: 10.1002/14651858.CD007662.pub2.

Author Information

  1. 1

    University of British Columbia, Department of Psychiatry, Vancouver, British Columbia, Canada

  2. 2

    University of Cape Town, Department of Psychiatry and Mental Health, Cape Town, South Africa

  3. 3

    Queen Elizabeth II Hospital, National Obsessive Compulsive Disorders Treatment Service, Welwyn Garden City, Hertfordshire, UK

  4. 4

    University of Cambridge, Department of Psychiatry, Cambridge, UK

*Dan J Stein, Department of Psychiatry and Mental Health, University of Cape Town, Education Centre, Valkenberg Hospital, Private Bage X1, Observatory, Cape Town, 7925, South Africa. dan.stein@uct.ac.za.

Publication History

  1. Publication Status: New
  2. Published Online: 8 NOV 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Description of the condition

Trichotillomania (TTM) is characterised by recurrent hair-pulling (APA 2012). Two surveys of college students in the United States have attempted to estimate the prevalence of TTM in this population; one survey of 2579 students reported lifetime prevalence rates as 0.6% (Christenson 1991b), and in another survey of 711 students, 0.9% reported baldness and significant distress as a result of hair-pulling (Rothbaum 1993).

Patients with TTM often have low levels of self-esteem, low psychosocial functioning and other comorbid psychiatric disorders, especially mood and anxiety disorders (Stein 2010). The Trichotillomania Impact Project has emphasised the immense distress and impairment associated with chronic hair-pulling (Woods 2006a).

The introduction of TTM into the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) encouraged treatment studies to proceed. In DSM-III-R, TTM was conceptualised as an Impulse-Control Disorder. Trichotillomania, kleptomania, pyromania and other conditions in the category were characterised by failure to resist an impulse, drive or temptation to perform an act that is harmful to the self or others (APA 1987). TTM remained under Impulse-Control Disorders in DSM-IV.

Some overlap has been noted between TTM and conditions such as obsessive-compulsive disorder (OCD) (Grant 2007). Many patients report that hair-pulling is preceded by urges and that hair-pulling involves ritualistic behaviours redolent of OCD (Swedo 1992). Early work suggests that both TTM and OCD respond to selective serotonin reuptake inhibitors (SSRIs) (Swedo 1989). This kind of work led to the inclusion of TTM in a new section of DSM-5, entitled "Obsessive-Compulsive and Related Disorders" (APA 2012).

At the same time, important differences between TTM and OCD may be seen in treatment response. TTM is not characterised by obsessional thoughts, and greater overlap may be evident with other obsessive-compulsive spectrum disorders, such as skin-picking and tic disorders (Stein 2010). Findings that TTM responds to low-dose antipsychotics and not to SSRIs are redolent of findings on the pharmacotherapy of tic disorders.

Based on the diagnostic criteria presented in DSM-5 (APA 2012), a diagnosis of TTM requires that recurrent hair-pulling must result in hair loss (criterion A). Evidence of an attempt to decrease or stop hair-pulling must also be present (criterion B). Furthermore, the diagnosis of TTM can be made only if hair-pulling is not better accounted for by another disorder (e.g. in response to a delusion, or as part of a body dysmorphic disorder) and is not a result of a general medical condition (criterion C). Finally, for a diagnosis of TTM, recurrent hair-pulling must cause significant distress or impairment of functioning (criterion D).

 

Description of the intervention

Several different pharmacotherapy and psychotherapy interventions have been studied in the treatment of TTM. Medications, cognitive-behavioural therapy (CBT) and their combination have been studied in a number of randomised controlled trials (RCTs) to date (Bloch 2007). Medication classes that have been studied in TTM include selective serotonin reuptake inhibitors (SSRIs: Christenson 1998; Gadde 2007; Iancu 1996; Koran 1992; Stanley 1991; Stanley 1997; Winchel 1992), serotonin-noradrenaline reuptake inhibitors (SNRIs: Ninan 1998), serotonergic tricyclic antidepressants (TCAs: Black 1992; Pollard 1991), antipsychotic agents, opioid agents, anticonvulsant agents and the glutamate modulator, N-acetylcysteine (NAC: Epperson 1999; Lochner 2006; Stewart 2003; Van Ameringen 1999).

Psychotherapy (specifically, habit-reversal therapy (HRT)) may have efficacy in the treatment of TTM. A meta-analysis by Bloch 2007 involving 59 completers in three RCTs compared HRT versus wait-list/placebo-control conditions and found a statistically significant benefit of HRT (Bloch 2007; Ninan 2000; Van Minnen 2003; Woods 2006b).

 

How the intervention might work

The psychobiology of TTM has been investigated increasingly in recent decades, with particular focus on neuroimaging research. In a positron emission tomography (PET) study, normalised resting cerebral glucose metabolic rates were found to be increased in the bilateral cerebellum and the right parietal cortex of study participants with trichotillomania (N = 10) compared with healthy controls (N = 20) (Swedo 1991). In a magnetic resonance imaging (MRI) study of TTM participants (N = 18) and healthy controls (N = 19), TTM participants showed an increase in grey matter density in several brain regions involved in affect regulation, motor habits and top-down behavioural inhibition (Chamberlain 2008). Subsequent MRI research has suggested an association between white matter tract abnormalities in TTM and symptom severity (Roos 2013). In a functional neuroimaging study using single-photon emission computed tomography (SPECT), 12 weeks of treatment with 20 mg of citalopram, titrated to a maximum dose of 60 mg, was associated with reduced activation in frontal and striatal regions (Stein 2002). Thus it is possible that serotonin reuptake inhibitors or other psychotropic agents may be useful in normalising the neural circuitry that mediates TTM, and in reducing hair-pulling.

 

Why it is important to do this review

A 2007 review of pharmacological treatment for TTM concluded that no consistent evidence supports the efficacy of any pharmacological agent in the treatment of trichotillomania (Bloch 2007). An updated systematic review of pharmacotherapy for trichotillomania, using the methodology of The Cochrane Collaboration, would be useful in reassessing the relevant evidence base. A systematic synthesis of treatment data may serve as the basis for future treatment guidelines, while assisting clinicians in effectively managing this disorder and identifying gaps in the current research base.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

To assess the effects of medication for trichotillomania in adults compared with placebo or other active agents.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Criteria for considering studies for this review

 

Types of studies

All published and unpublished RCTs, including studies with multiple treatment groups, cross-over trials, and cluster RCTs, were considered for the review. Pseudo-randomised trials were excluded in the interest of minimising bias.

 

Types of participants

 

Participant characteristics

Participants meeting the DSM-III-R (APA 1980) (or later) criteria for trichotillomania were included in this review. The review authors did not exclude trials consisting of participants who failed to satisfy the criteria of tension preceding the onset of hair-pulling (criterion B) and pleasure, gratification or relief following hair-pulling (criterion C), as patients without these symptoms may nevertheless present with clinically significant hair-pulling (Christenson 1991b; Du toit 2001).

No restrictions in terms of age, gender or race were applied.

 

Comorbidities

We did not exclude participants with other psychiatric comorbidities.

 

Setting

No restrictions were placed on study setting.

 

Subsets of participants

Trials that include a subset of participants and meet study inclusion criteria were also included in the analysis.

 

Types of interventions

 

Experimental interventions

We planned to group specific medication interventions according to medication class. We included trials of medications in any of the following classes as monotherapy.

  1. Selective serotonin reuptake inhibitors (SSRIs) (e.g. citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline).
  2. Serotonin-noradrenaline reuptake inhibitors (SNRIs) (e.g. venlafaxine).
  3. Serotonergic tricyclic antidepressants (TCAs) (e.g. clomipramine).
  4. Other tricyclic antidepressants (TCAs) (e.g. amitriptyline, desipramine, imipramine).
  5. Monoamine oxidase inhibitors (MAOIs) (e.g. brofaromine, moclobemide, phenelzine).
  6. Mood stabilisers (e.g. lithium).
  7. Antipsychotics (e.g. haloperidol, olanzapine, quetiapine, risperidone).
  8. Opioid antagonists (e.g. naltrexone).
  9. Anticonvulsants (e.g. gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate).
  10. Nutraceuticals (e.g. N-acetylcysteine, inositol).
  11. Benzodiazepines (e.g. alprazolam, bromazepam, clonazepam).

 

Control conditions

  1. Placebo.
  2. Any agent in the medication classes listed above.

 

Types of outcome measures

 

Primary outcomes

  1. Treatment response based on the Clinical Global Impressions scale (CGI-I), a widely used categorical measure of treatment response in which responders are defined as having a change item score of 1 = 'very much improved' to 7 = 'very much worse' (Guy 1976). We planned to include both continuous data for scores and categorical data if articles reported 'responders' versus 'non-responders'.
  2. Reduction of symptom severity based on outcome measures such as the Massachussetts General Hospital Hair-pulling Scale (MGH), where available.

 

Secondary outcomes

  1. Responsiveness to treatment of comorbid symptoms of depression, quantified by the commonly employed Beck Depression Inventory scale (BDI) (Beck 1961), Hamilton Depression Rating scale (HAM-D) (Hamilton 1960) or Montgomery-Asberg Depression Rating scale (MADRS) (Montgomery 1979).
  2. Tolerability of treatment using the following surrogate measures of medication acceptability.
    1. Total proportion of people who withdrew from RCTs because of adverse events.
    2. Most common drug-related adverse events (> 20% of participants given the medication affected), as well as significant differences between medication and control groups in the occurrence of drug-related adverse events.
  3. Quality of life measures such as the Quality of Life Enjoyment and Satisfaction Questionnaire (QoL-ESQ), as well as measures of functional disability such as the Sheehan Disability Scale (SDS) (which includes subscales that assess impairment related to work, social life and family) (Sheehan 1996) were included when provided.

 

Timing of outcome assessment

When studies reported response rates at various time points of the trial, treatment indices will be subdivided as follows.

  1. Early response—between one and four weeks; the time point closest to two weeks was given preference.
  2. Acute phase treatment response—between six and 12 weeks; the time point given in the original study as the study endpoint was given preference.
  3. Follow-up response—between four and six months; the time point closest to 24 weeks was given preference.

The acute phase treatment response, that is between six and 12 weeks, was our primary outcome of interest.

 

Search methods for identification of studies

No date or language restrictions were applied to the search for RCTs in any of the sources listed below.

 

Electronic searches

1. CCDAN's Specialised Register (CCDANCTR)
The Cochrane Depression, Anxiety and Neurosis Group (CCDAN) maintains two clinical trial registers at its editorial base in Bristol, UK, a references register and a studies based register. The CCDANCTR-References Register contains over 31,000 reports of trials in depression, anxiety and neurosis. Approximately 65% of these references have been tagged to individual, coded trials. The coded trials are held in the CCDANCTR-Studies Register and records are linked between the two registers through the use of unique Study ID tags. Coding of trials is based on the EU-Psi coding manual. Please contact the CCDAN Trials Search Co-ordinator for further details.

Reports of trials for inclusion in the Group's registers are collated from routine (weekly), generic searches of MEDLINE (1950 to date), EMBASE (1974 to date) and PsycINFO (1967 to date), as well as quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL) and review-specific searches of additional databases. Reports of trials are also sourced from international trials registers c/o the World Health Organization’s trials portal (ICTRP), drug companies, the hand-searching of key journals, conference proceedings and other (non-Cochrane) systematic reviews and meta-analyses.

Details of CCDAN's generic search strategies can be found on the Group's web site.

The CCDANCTR-Studies Register was searched by the Trials Search Co-ordinator (TSC: SD) using the following terms:
Condition = trichotillomania

The CCDANCTR-References Register was searched by the TSC to retrieve additional untagged references using the free-text term: trichotillomani*

Searches were conducted to 31 July 2013.

2) The Cochrane Central Register of Controlled Trials (CENTRAL)
The TSC carried out an additional search of CENTRAL using the term "trichotillomania" (31 July 2013).

3) MEDLINE, EMBASE, PsycINFO
We ran earlier searches on MEDLINE via PubMed (1966-2013), EMBASE (1980-2013) and PsycINFO (1970-2013), see Appendix 1.

4) Trial registers
Ongoing trials were located using the World Health Organiztation's (WHO) trials portal (ICTRP), ClinicalTrials.gov and Controlled-trials.com using the term '"trichotillomania" (31 July 2013).

5) Other electronic databases
We also ran searches (for "trichotillomania") on the following electronic databases:

a) ProQuest Dissertations and Theses Database, and DissOnline. The search was performed on 28 June 2011 (years covered not stated by database host) and yielded 26 articles and 21 articles, respectively (none were RCTs meeting inclusion criteria).

b) The Cumulative Index to Nursing and Allied Health Literature (CINAHL). The search was performed 28 June 2011 (1981-2011) and yielded 150 results, none of which were related to trichotillomania.

c) Regional electronic databases: African Index Medicus (dates covered not stated by database host), Informit Health Collection (Australia) (1970-2012), Index Medicus for the Eastern Mediterranean Region (1984-2012), IndMed (India) (1985-2012), KoreaMed (1997-2012), Ukraine and the Russian Federation - panteleimon (1998-2012) and Western Pacific Region Index Medicus (years covered not stated by database host). These searches were performed on 27 June 2011 and update searches performed on 14 May 2012.

d) Latin America and the Caribbean (LILACS) was searched in English, Spanish and Portuguese using the following terms: "trichotillomania" and "tricotilomania" (years covered not stated by database host). The search was performed on 15 August 2011 and an updated search performed on 14 May 2012.

 

Searching other resources

Reference lists
The bibliographies of all identified trials were scanned for additional studies.

Correspondence
Published and unpublished trials were obtained from key researchers, as identified by the frequency with which they are cited in the bibliographies of RCTs and open-label studies.

Grey literature searches

One review author (RR) performed the grey literature searching using the search term "trichotillomania" in all cases. The search included the following:

1) OpenSIGLE (no results found), The Healthcare Management Information Consortium (HMIC) (no results found), the National Technical Information Service (NTIS) (no results found) and Psycextra (16 results, none of which were RCTs meeting inclusion criteria). These searches were performed on 28 June 2011.

2) Pharmaceutical industry trial registers were identified on the basis of the pharmaceutical companies that produce the drugs that have been studied for TTM. Other registers were included on the basis that they were free and available to search. The following pharmaceutical industry trial registers were searched on 13 June 2011 and update searches performed on 14 May 2012: AstraZeneca, Bristol-Myers Squibb, Eli lilly, GlaxoSmithKline, Novartis, Roche and Pfizer/Wyeth; no results were found.

3) Abstracts of the American Psychiatric Association (APA) (2004-2010) and the European College of Neuropsychopharmacology annual meetings were searched (2006-2010), no results found.

4) A cited reference search was conducted on 28 June 2011 using Web of Science and yielded 776 articles (none of which were RCTs meeting inclusion criteria).

 

Data collection and analysis

 

Selection of studies

Two review authors (RR and TA) independently examined the titles and abstracts of all studies obtained through the search strategy. The same two review authors obtained and independently assessed the full text of relevant articles that appeared to meet the inclusion criteria. The full eligibility criteria for inclusion in the review were then applied to the full-text articles by each review author independently. Any conflicts of opinion were discussed and arbitrated by another review author (DJS) until consensus was reached.

 

Data extraction and management

The same review authors who selected studies for inclusion (RR and TA) independently collected the data. Any disagreements regarding the data collection procedures were resolved by discussion with a third review author (DJS). Paper data extraction sheets were created for the purpose of manually recording descriptive information, summary statistics of the outcomes, quality scale ratings and associated commentary. These data were then entered into Review Manager (RevMan) software, which was used to conduct the meta-analysis. When information was missing, the review authors contacted investigators by email in an attempt to obtain this information. No reports required translation.

The following information was collected from each study.

  1. Description of the trials, including the primary researcher, the year of publication and the source of funding.
  2. Characteristics of the interventions, including the number of participants randomly assigned to the treatment and control groups, the number of total dropouts per group and the number who dropped out because of adverse effects.
  3. Characteristics of trial methodology, including the diagnostic (e.g. DSM-IV (APA 2000)) and exclusionary criteria employed, the screening instrument used (e.g. the Structured Clinical Interview for DSM-IV (SCID) (Spitzer 1996)) for the primary and comorbid diagnoses, the presence of comorbid major depressive disorder (MDD), the use of a placebo run-in, whether a minimal severity criterion was employed and the number of centres involved.
  4. Characteristics of participants, including gender distribution and age distribution, mean length of time since diagnosis with trichotillomania, whether participants have been treated with the medication in the past (treatment naivety), the number of participants in the sample with MDD and the baseline severity of trichotillomania, as assessed by the primary outcome measure reported in the trial or another commonly employed scale.
  5. Outcome measures employed (primary and secondary) and summary continuous (means and standard deviations) and dichotomous (number of responders) data. Additional information was included, such as whether data reflected the intent-to-treat (ITT) with last observation carried forward (LOCF) or completer/observed cases (OC) sample, and the minimal period required for inclusion of participants in the LOCF analyses. Other methods of estimating the outcome for participants who dropped out of the study, such as the mixed effects (ME) model, were recorded.

 

Main comparisons

The review categorised the comparisons as follows.

Comparison 1: SSRIs versus placebo

1.1 Fluoxetine versus placebo

1.2 Sertraline versus placebo

Comparison 2: TCAs versus placebo

2.1 Clomipramine versus placebo

Comparison 3: TCAs versus other active agent

3.1 Clomipramine versus desipramine

Comparison 4: NAC versus placebo

Comparison 5: Antipsychotics versus placebo

Comparison 6: Opioid antagonists versus placebo

 

Assessment of risk of bias in included studies

RR and TA independently examined the components of each included trial for risk of bias using a standard form. This form included information on sequence generation, allocation concealment, blinding (participants, personnel and outcome assessor), incomplete outcome data, selective outcome reporting and other sources of bias. The methodological components of the trials were assessed as having a low, high or unclear risk of bias, as per the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). When differences arose, these were resolved by discussions with the third review author (DJS).

Sequence generation

  1. Low risk: Investigators described a random component in the sequence generation process such as the use of a random number table, coin tossing, cards or envelope shuffling.
  2. High risk: Investigators described a non-random component in the sequence generation process such as the use of odd or even date of birth, algorithm based on the day/date of birth or hospital or clinic record number.
  3. Unclear: Insufficient information was provided to permit judgement of the sequence generation process.

Allocation concealment

  1. Low risk: Participants and investigators enrolling participants cannot foresee assignment (e.g. central allocation or sequentially numbered, opaque, sealed envelopes).
  2. High risk: Participants and investigators enrolling participants can foresee upcoming assignment (e.g. open random allocation schedule, such as a list of random numbers, or envelopes that were unsealed or non­opaque or were not sequentially numbered).
  3. Unclear: Insufficient information was provided to permit judgement of allocation concealment, or the method was not described.

Blinding

  1. Low risk: Blinding of participants, key study personnel and outcome assessor is described, and it is unlikely that blinding could have been broken; or lack of blinding is described in a situation where non-blinding is not likely to introduce bias.
  2. High risk: No blinding or incomplete blinding is described, and the outcome is likely to be influenced by lack of blinding.
  3. Unclear: Insufficient information is provided to permit judgement of adequacy or otherwise of the blinding.

Incomplete outcome data

  1. Low risk: No outcome data are missing, reasons for missing outcome data are unlikely to be related to true outcome, or missing outcome data are balanced in number across groups.
  2. High risk: Reason for missing outcome data is likely to be related to the true outcome, with imbalance in numbers across groups or in reasons for missing data.
  3. Unclear: Reporting of attrition or exclusions is insufficient.

Selective outcome reporting

  1. Low risk: A protocol that clearly states the primary outcome as the same as in the final trial report is available.
  2. High risk: The primary outcome differs between the protocol and the final trial report.
  3. Unclear: No trial protocol is available, or reporting is insufficient to determine whether selective reporting is present.

Other sources of bias

  1. Low risk: No evidence suggests bias from other sources.
  2. High risk: Potential bias from other sources is present (e.g. early stopping of trial, fraudulent activity, extreme baseline imbalance or bias related to specific study design).
  3. Unclear: Insufficient information is provided to permit judgement of adequacy or otherwise of other forms of bias.

 

Measures of treatment effect

 

Dichotomous data

We planned to calculate the risk ratio (RR) and the 95% confidence interval (CI) for the dichotomous outcome of interest (CGI-I or related measure). Where interventions increase the likelihood of events odds ratios will be larger than risk ratios and to avoid misinterpretation we used risk ratios (Higgins 2011). This is especially the case when the occurrence of the outcome of interest is common, with an expected response greater than 20% (as anticipated in this review) (Deeks 2008). For positive results, we planned to calculate the number needed to treat for an additional beneficial outcome (NNTB). NNTB is defined as the inverse of the absolute risk difference due to the medication intervention. In this review, we planned to use NNTB to indicate the number of participants who require treatment with medication, relative to a control, before a single additional participant in the medication group responds to treatment.

 

Continuous data

We planned to calculate mean difference (MD) for continuous summary data derived from the same scale. In cases in which different scales are employed, such as in the assessment of comorbid depression on MADRS and HAM-D, the standardised mean difference (SMD) will be determined for each outcome. This method of analysis standardises the differences between means of the treatment and control groups in terms of the variability observed in the trials.

 

Skewed data

When evidence indicated that data were skewed, we planned to obtain individual participant data (when possible) for the purpose of normalising the data through the use of log transformation techniques. If this proved unsuccessful, those studies that provided skewed data would be excluded from the analysis. For the purposes of this review, the following constituted evidence of skewness: cases in which the difference between the observed mean and the lowest possible value or the highest possible value on the scale is less than twice as large as the standard deviation (Deeks 2008), or cases in which data are reported as skewed by the authors.

 

Unit of analysis issues

 

Studies with multiple treatment groups

In future updates of the review, if trials with three or more arms are identified, it may be appropriate to do a multi-arm trial analysis wherein the placebo group would be split and shared between two or more groups with smaller sample sizes. In this way, the two or more intervention groups can be analysed as subgroups (Higgins 2011).

 

Cross-over trials

We planned to include cross-over trials in the calculation of outcomes of interest only (1) when it was possible to extract medication and placebo/comparator data from the first treatment period, and (2) when inclusion of data from both treatment periods was justified by a washout period of sufficient duration as to minimise the risk of carry-over effects. An adequate washout period was defined in accordance with clinical practice as at least two weeks for all agents, with the exception of fluoxetine, for which a minimum washout period of four weeks was required, given the long plasma half-life of this agent. Cross-over trials that lacked a washout period were included if the agents compared were of the same class and had similar properties. For trials in which the washout period was regarded as adequate, we planned to include data from both periods when it was possible to determine the standard error of the mean difference in response between groups (Elbourne 2002). We planned to obtain the summary statistics required to derive the standard error from the trial report, or, for trials for which this information was missing, we planned to impute the summary statistics by averaging the relevant statistic from other included cross-over trials with comparable control conditions.

 

Cluster randomised trials

For cluster RCTs, we would apply an intraclass correlation (ICC) for the sample to take into account the effect of clustering. We would use the ICC reported in the publication, or, if necessary, we would contact study authors to request this information. If we were unable to obtain this information, we would calculate an ICC estimate using the average of the ICCs obtained from the other studies included in the analysis. We would undertake the analysis by using generic inverse variance (GIV).

 

Dealing with missing data

We planned to conduct all analyses of dichotomous data as ITT. We planned to use the total number of participants randomly assigned to the different comparison groups as the denominator in comparisons of treatment response. Only data from trials that provide information on the original group size (before dropouts) were eligible for inclusion in the analyses of treatment response. We planned to give preference to the inclusion of summary statistics for continuous outcome measures derived from ME models, followed by LOCF and OC summary statistics (in that order). This is in line with evidence that ME methods are more robust to bias than LOCF analyses (Verbeke 2000).

 

Assessment of heterogeneity

For trials in which the methods and clinical characteristics were sufficiently homogeneous that they could be combined, we assessed statistical heterogeneity of treatment response and symptom severity visually from the forest plot. This helped the review authors to determine whether differences between the results of trials were greater than would be expected by chance alone. We assessed heterogeneity by using the Chi2 test of heterogeneity. If the Chi2 test has a P value of less than 0.10, this is interpreted as evidence of heterogeneity, given the low power of the Chi2 statistic when the number of trials is small (Deeks 2008).

In addition, the I2 heterogeneity statistic as reported by RevMan was used to test the robustness of the Chi2 statistic to differences in the number of trials included in the groups compared within each subgroup analysis (Higgins 2003).

Thresholds for the interpretation of I2 can be misleading because the importance of inconsistency depends on several factors. A rough guide for interpretation was followed.

  • 0% to 40%: might not be important.
  • 30% to 60%: may represent moderate heterogeneity.
  • 50% to 90%: may represent substantial heterogeneity.
  • 75% to 100%: may represent considerable heterogeneity.

Differences on continuous measures in medication efficacy between these groups were assessed by means of Deeks’ stratified test of heterogeneity (Deeks 2001). This method subtracts the sum of the Chi2 statistics available for each of the subgroups in the study from the Chi2 statistic available for all of the trials, to obtain a measure (Qb) of heterogeneity between groups. We planned to determine differences in treatment response on the CGI-I by noting whether the confidence intervals for the effect sizes of the subgroups overlap. This method was chosen in preference to the stratified test because of inaccuracies in the calculation in RevMan of the Chi2 statistic for dichotomous measures (Deeks 2008).

 

Assessment of reporting biases

Publication is not necessarily related to study quality, and indeed publication may imply certain biases (Dickersin 1992; Song 2000). We planned to assess small-sample effects (including publication bias) through visual inspection of a funnel plot of treatment response. This is possible, however, only when more than ten studies are included in the funnel plot.

 

Data synthesis

In conducting a meta-analysis, we planned to obtain categorical and continuous treatment effects from a random-effects model (the random-effects model includes both within-study sampling error and between-studies variation in determining the precision of the confidence interval around the overall effect size, whereas the fixed-effect model takes only within-study variation into account). The outcomes are expressed in terms of an average effect size for each subgroup, as well as by means of 95% confidence intervals.

In future updates, if appropriate, we may consider using 'multiple-treatments meta-analyses' (MTM) methodology to compare and analyse intervention groups across studies. This method relies on the strong assumption that studies of different comparisons are similar in all ways other than the interventions being compared (Higgins 2011).

 

Subgroup analysis and investigation of heterogeneity

We planned to undertake subgroup analyses to assess the degree to which methodological differences between trials might have systematically influenced differences observed in primary treatment outcomes. The a priori subgroups that we planned to explore included the following.

  1. Involvement of participants from a single centre or from multiple centres. Single-centre trials are more likely to be associated with lower sample size but less variability in clinician ratings.
  2. Whether trials were industry funded. In general, published trials that are sponsored by pharmaceutical companies appear more likely to report positive findings than trials that are not supported by for-profit companies (Als-Nielsen 2003; Baker 2003).

In addition, the following criterion was used to assess the extent of clinical sources of heterogeneity.

  1. Whether the sample included participants diagnosed with major depression. Such an analysis might assist in determining the extent to which the efficacy of a medication agent used in treating trichotillomania is independent of its ability to reduce symptoms of depression—an important consideration given the classification of many of these medications as antidepressants.

 

Sensitivity analysis

Sensitivity analyses determine the robustness of the review authors' conclusion to methodological assumptions made in conducting the meta-analysis. We planned to conduct sensitivity analyses to determine whether treatment response varies as a function of:

  1. the use of treatment response versus non-response as an outcome statistic. This comparison may be necessary in the light of evidence that treatment response may result in less consistent outcome statistics than non-response (Deeks 2002) when the control group event rate is higher than 50%. This sensitivity analysis would accordingly be performed only if most trials report a control group event rate higher than 50%;
  2. the exclusion of participants who were lost to follow-up (LTFU). We planned to determine this through a "worst case/best case" scenario (Deeks 2008). In the worst case, all missing data for the treatment group are recorded as non-responders, whereas in the best case, all missing data for the control group are treated as non-responders. Should conclusions regarding treatment efficacy not differ between these two comparisons, it can be assumed that missing data in trial reports do not have a significant influence on outcome;
  3. the exclusion of results based on LOCF or OC;
  4. the exclusion of cross-over trials;
  5. the exclusion of cluster-randomised trials; or
  6. varying ICCs in cluster-randomised trials.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Description of studies

 

Results of the search

Our initial search yielded 1106 records; after examination of their titles and abstracts, the full texts of 12 studies were analysed for inclusion; eight met the inclusion criteria for the review (Figure 1).

 FigureFigure 1. PRISMA flow diagram.

We attempted to contact the principal investigators of each of the eight included studies to obtain or verify information (seven people, as Christenson authored two studies—Christenson 1991a; Christenson 1994). We were successful in contacting and obtaining information from six of the seven study authors.

 

Included studies

See Characteristics of included studies.

 

Design

Of the eight studies identified as eligible for the review, all were RCTs. Seven trials were conducted in the United States and one in Canada (Van Ameringen 2010). Three of the trials used a cross-over design (Christenson 1991a, Streichenwein 1995; Swedo 1989), and five trials used a parallel-group design (Christenson 1994; Dougherty 2006; Grant 2009; Ninan 2000; Van Ameringen 2010). The three cross-over trials were 17 weeks, 27 weeks and 10 weeks in duration, respectively. Of the parallel-group trials, one was six weeks in duration, one was nine weeks in duration and three were 12 weeks in duration. All of the studies were published in English language journals, with the exception of one (Christenson 1994), which was presented as a conference abstract. Four studies were funded by pharmaceutical companies (Dougherty 2006; Ninan 2000; Streichenwein 1995; Van Ameringen 2010).

 

Sample sizes

The eight studies involved a total of 204 participants with a mean sample size of 25.25, a median of 20 and a range from the smallest sample size of 13 to the largest of 50.

 

Setting

All studies were single-centre trials, and all participants were seen on an outpatient basis.

 

Participants

Five of the eight trials report using DSM-III-R (or later) criteria to select participants (Christenson 1991a; Dougherty 2006; Grant 2009; Ninan 2000; Van Ameringen 2010); the other three trials do not report the specific criteria employed in participant selection (Christenson 1994; Streichenwein 1995; Swedo 1989). Two trials did not require DSM criteria B and C for inclusion in the trials (i.e. a sense of tension before and a sense of relief after hair-pulling) (Christenson 1991a; Grant 2009). Of the six trials that reported the gender of participants, five reported the proportion of female participants as 75% to 100%, reflecting female predominance in TTM (Christenson 1991a; Grant 2009; Ninan 2000; Streichenwein 1995; Swedo 1989). The mean age of participants in the six trials that reported this variable was between 30 and 40 years (Christenson 1991a; Grant 2009; Ninan 2000; Streichenwein 1995; Swedo 1989; Van Ameringen 2010). Rates of comorbid psychiatric conditions were reported in five trials; rates of major depressive disorder or a history of major depressive disorder ranged from 18.8% to 46.2% in three trials (Christenson 1991a; Grant 2009; Swedo 1989); rates of anxiety disorders ranged from 20.0% to 75.0% in five trials (Christenson 1991a; Grant 2009; Streichenwein 1995; Swedo 1989; Van Ameringen 2010). Two studies reported rates of 'another impulse-control disorder' as 20.0% and 36.0% (Grant 2009; Van Ameringen 2010). The same two studies reported rates of eating disorders of 4.0% and 2.0%, respectively. One study reported a significant rate of drug and alcohol use among participants (30.8%; Swedo 1989).

 

Interventions

The eight studies included three studies of SSRIs (two fluoxetine (Christenson 1991a; Streichenwein 1995) and one sertraline (Dougherty 2006)); two of serotonergic TCAs (clomipramine (Ninan 2000; Swedo 1989)); one of an antipsychotic (olanzapine (Van Ameringen 2010)); one of a glutamate modulator (N-acetylcysteine (Grant 2009)); and one of an opiate antagonist (naltrexone (Christenson 1994)). A placebo comparison group was employed in all but one trial, which involved an active agent comparator (Swedo 1989). Of the three trials employing a cross-over design (Christenson 1991a, Streichenwein 1995; Swedo 1989), two involved a five-week washout period before cross-over between fluoxetine and placebo (Christenson 1991a; Streichenwein 1995). In Swedo 1989, a washout period was not employed, as desipramine was used as an active control and has similar properties to the intervention (clomipramine), so that a washout period was not deemed necessary. All trials employed gradual dose progression, except for that of naltrexone (Christenson 1994), for which a constant dose was given throughout the trial.

 

Outcomes

Two trials employed an untitled scale that measured five aspects of self-reported TTM severity (Christenson 1991a; Streichenwein 1995); three trials employed the validated National Institute of Mental Health (NIMH) Trichotillomania Severity Scale (TSS) and Trichotillomania Impairment Scale (TIS) (Christenson 1994; Ninan 2000; Swedo 1989); three trials employed the Massachusetts General Hospital Hair-pulling Scale (MGH-HPS) (Dougherty 2006; Grant 2009; Van Ameringen 2010); two trials employed the Psychiatric Institute Trichotillomania Scale (PITS) (Dougherty 2006; Grant 2009); one trial employed the Trichotillomania Impact Scale (TTMIS) (Dougherty 2006); three trials employed the Clinical Global Impression (CGI) Scale (Dougherty 2006; Grant 2009; Van Ameringen 2010); and one trial employed the Yale-Brown Obsessive-Compulsive Scale for TTM (Van Ameringen 2010).

Secondary outcome measures employed were the Hamilton Rating Scale for Depression (HAM-D) (Christenson 1991a; Dougherty 2006; Grant 2009; Streichenwein 1995), the Hamilton Rating Scale for Anxiety (HAM-A) (Grant 2009), the Beck Depression Inventory (Christenson 1991a; Dougherty 2006; Ninan 2000; Streichenwein 1995; Van Ameringen 2010), the Beck Anxiety Inventory (Dougherty 2006; Van Ameringen 2010), the State-trait Anxiety Inventory (Ninan 2000), the NIMH Global Assessment Scales for Depression and Anxiety (Swedo 1989), the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) (Dougherty 2006; Van Ameringen 2010), the Quality of Life Inventory (Grant 2009) and the Sheehan Disability Scale (SDS) (Grant 2009; Van Ameringen 2010).

 

Excluded studies

See Characteristics of excluded studies.

Four studies were excluded for the following reasons: non-RCT design (Riley 1993); waiting-list control group instead of placebo (Van Minnen 2003); outcome measured was neurocognitive performance (motor inhibitory control), not trichotillomania symptom severity (Chamberlain 2010); paediatric population (Bloch 2013).

 

Ongoing studies

No ongoing RCTs of the pharmacotherapy for TTM were identified.

 

Studies awaiting classification

No studies are awaiting classification.

 

Risk of bias in included studies

Full details of the determination of risk of bias can be found in Characteristics of included studies and in Figure 2 and Figure 3.

 FigureFigure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

 

Random sequence generation

Risk of bias arising from the method of generation of the allocation sequence was rated as low in seven studies (Christenson 1991a; Christenson 1994; Dougherty 2006; Grant 2009; Streichenwein 1995; Swedo 1989; Van Ameringen 2010). These studies reported generating the sequence by computer or by a random number table, or such information was obtained from the first author. Ninan 2000 did not disclose a method of randomisation; therefore the presence of selection bias is unclear for this study.

 

Allocation concealment

Risk of bias arising from the method of allocation concealment was rated as low in seven studies (Christenson 1991a; Christenson 1994; Dougherty 2006; Grant 2009; Streichenwein 1995; Swedo 1989; Van Ameringen 2010). These studies reported the use of central allocation (e.g. pharmacy-controlled allocation) or this information was obtained from the first author. Ninan 2000 did not disclose a method of allocation; therefore the presence of selection bias is unclear for this study.

 

Blinding

 

Blinding of participants and personnel (performance bias)

Risk of bias arising from lack of blinding of participants and personnel was rated as low for all studies. Most studies reported using a placebo or other form of control that was identical in appearance to the intervention; if not reported, it can be assumed that participants were blinded in placebo-controlled studies (Christenson 1991a; Christenson 1994; Dougherty 2006; Grant 2009; Ninan 2000; Streichenwein 1995; Swedo 1989; Van Ameringen 2010).

 

Blinding of outcome assessors (detection bias)

Risk of bias arising from lack of blinding of outcome assessors was rated as low for all studies. Most studies reported blind outcome assessment; if not, this information was obtained from the first author (Christenson 1991a; Christenson 1994; Dougherty 2006; Grant 2009; Ninan 2000; Streichenwein 1995; Swedo 1989; Van Ameringen 2010).

 

Incomplete outcome data

Risk of attrition bias was rated as low in four trials (Christenson 1991a; Grant 2009; Swedo 1989; Van Ameringen 2010). Risk of attrition bias was rated as high in three trials, in which attrition was greater than 10% overall and/or was differentially distributed between intervention and control groups (Dougherty 2006; Ninan 2000; Streichenwein 1995). Risk of attrition bias was not reported for the Christenson 1994 trial and therefore was rated as unclear.

 

Selective reporting

Trial protocols were not obtained for any of the trials; therefore reporting bias was rated as unclear for all trials (Christenson 1991a; Christenson 1994; Dougherty 2006; Grant 2009; Ninan 2000; Streichenwein 1995; Swedo 1989; Van Ameringen 2010).

 

Effects of interventions

For several reasons, we did not conduct meta-analyses in this review; instead we report separately the results of individual studies. For two classes of medications—the SSRIs and the TCAs—more than one study is included. Within the SSRI class, two studies of fluoxetine versus placebo presented data using F, df and P values (Christenson 1991a; Streichenwein 1995). Neither of the principal authors of these studies were able to provide the original data from the trials to make individual participant analysis (IDP) possible; therefore the results of these trials are described individually. For the third SSRI study, a sertraline study, mean change scores for the primary outcome measure were obtained from the first author (Dougherty 2006). None of the SSRI trials demonstrated a statistically significant treatment response.

Two studies of clomipramine (TCA) are included in the review. One was a cross-over trial with head-to-head comparison of clomipramine and desipramine (Swedo 1989), and the other was a parallel-arm trial of clomipramine versus placebo (Ninan 2000). It is not appropriate to pool data from a study that is placebo-controlled with data from a study that is a head-to-head comparison; therefore the results of these two trials are reported separately.

Results of the studies of naltrexone (Christenson 1994), N-acetylcysteine (Grant 2009) and olanzapine (Van Ameringen 2010) are reported individually.

 

Comparison 1: SSRIs versus placebo

 

Primary outcomes

 
Treatment response/reduction in symptom severity

 
Comparison 1.1: Fluoxetine versus placebo

The study by Christenson 1991a did not yield strong evidence that fluoxetine is effective when compared with placebo. The study authors report that the mean severity rating of hair-pulling between fluoxetine and placebo groups was not statistically significant, with F of 0.75, df of 6, 10 (P value = 0.62). The authors report that the difference in means for the severity rating of urge to pull hair was also not significant, with F of 0.45, df of 6, 10 (P value = 0.83). The mean number of hair-pulling episodes per week was less in the intervention group (15 compared with 37 in the placebo group), but this was not significant, with F of 1.41, df of 6, 10 (P value = 0.30). No evidence suggested that the intervention reduced mean estimated hair loss per week, with F of 0.29, df of 6, 10 (P value = 0.93).

The study by Streichenwein 1995, which used the same outcome measures as the Christenson study above, did not provide strong evidence that fluoxetine is effective when compared with placebo. No difference between the mean severity rating of hair-pulling for the intervention group and the placebo group was noted, with F of 0.48, df of 5, 74 (P value = 0.79). No difference between the mean severity rating of urge to pull hair was observed for the two groups, with F of 0.55, df of 5, 73 (P value = 0.74). The mean estimated number of hairs pulled per week was not significantly different between groups, with authors reporting F of 0.97, df of 5, 75 (P value = 0.44). Finally, the mean number of hair-pulling episodes per week was actually higher in the fluoxetine group than in the placebo group, which was reported as F of 1.05, df of 5, 74 (P value = 0.39).

 
Comparison 1.2: Sertraline versus placebo

Results of the initial 12-week phase of the Dougherty 2006 trial comparing sertraline versus placebo were not published, as this phase of the trial was not the focus of the study. We obtained from the first author the mean change scores on the primary outcome measure (the Massachusetts General Hospital Hair-pulling Scale (MGH-HPS))—mean change score for sertraline = -1.53, SD 5.54; mean change score for placebo = -1.06, SD 5.34. Our analysis did not provide strong evidence that sertraline is effective when compared with placebo (MD -0.47, 95% CI -4.30 to 3.36, P value = 0.81;  Analysis 1.1).

 

Secondary outcomes

 
Responsiveness to treatment of comorbid symptoms of depression

 
Comparison 1.1: Fluoxetine versus placebo

In the cross-over study by Christenson 1991a, mean baseline scores on both the Hamilton Rating Scale for Depression (HAM-D) and the Beck Depression Inventory (BDI) were below the threshold for clinical depression. Mean scores on the BDI were 3.9 at baseline and 2.9 at week six for the placebo phase and 3.0 at baseline and 2.4 at week six for the fluoxetine phase. The study reported no significant drug-by-period interactions with regard to Beck Inventory scores. Mean HAM-D scores for placebo were 4.9 at baseline and 3.6 at week six for the placebo phase and 3.4 at baseline and 4.4 at week six for the fluoxetine phase. A drug-by-period interaction was noted for the Hamilton Depression scores, but in the opposite direction of that anticipated; an improvement in depression was observed during the placebo phase and a worsening of depression during the fluoxetine phase (F = 5.13, df = 1, 15, P value = 0.04).

In the cross-over study by Streichenwein 1995, mean baseline scores on both the Hamilton Rating Scale for Depression (HAM-D) and the Beck Depression Inventory (BDI) were below the threshold for clinical depression. Scores from the fluoxetine and placebo treatment periods were combined, so that the effect of fluoxetine cannot be differentiated from the effect of placebo. No statistically significant drug-by-period interaction was reported for the HAM-D (F = 0.17, df = 2, 26, P value = 0.84) or for the BDI (F = 0.02, df = 2, 27, P value = 0.98).

 
Comparison 1.2: Sertraline versus placebo

For the third SSRI study, which compared sertraline versus placebo (Dougherty 2006), no data are available on symptoms of comorbid depression for the pharmacotherapy phase of the trial.

 
Tolerabilty of treatment

 
Comparison 1.1: Fluoxetine versus placebo

In the Christenson 1991a cross-over trial of fluoxetine versus placebo, one of 17 participants (5.9%) withdrew from the trial after developing urticaria during week four of fluoxetine. The most common adverse effect was nausea, which was reported in five of 17 participants taking fluoxetine (29.4%) and in two of 17 participants taking placebo (11.8%).

In the Streichenwein 1995 cross-over trial of fluoxetine versus placebo, one of 23 participants (4.3%) withdrew from the trial because of a severe serum sickness–like syndrome during week seven of fluoxetine. Other common adverse effects were categorised as central nervous system (CNS) and gastrointestinal (GIT) effects. CNS effects (including nightmares, insomnia, dizziness, irritability, anxiety and a feeling of doom) as a category affected 22 of 23 participants (95.7%) during the fluoxetine phase of the trial versus 16 of 23 participants (69.6%) during the placebo phase. GIT effects (including decreased appetite, diarrhoea, constipation, nausea, increased weight, abdominal pain and dyspepsia) as a category affected 14 of 23 participants (60.9%) in the fluoxetine phase of the trial and only three participants (13.0%) during the placebo phase.

 
Comparison 1.2: Sertraline versus placebo

For the third SSRI study, which compared sertraline versus placebo (Dougherty 2006), no data are available on adverse drug effects for the pharmacotherapy phase of the trial.

 
Responsiveness to treatment on quality of life measures

No data on quality of life measures are available for the SSRI trials (Christenson 1991a; Dougherty 2006; Streichenwein 1995)

 

Comparison 2: TCAs versus placebo

 

Primary outcomes

 
Treatment response/reduction in symptom severity

 
Comparison 2.1: Clomipramine versus placebo

In the study by Ninan 2000 of clomipramine versus placebo, scores on the CGI-I indicated that four of six participants in the clomipramine group were responders, compared with zero of five in the placebo group; this does not represent strong evidence that clomipramine is effective when compared with placebo (P value = 0.61) (responders were defined as those scoring 2 or less on the CGI-I). The same trial did not provide strong evidence for the effectiveness of clomipramine based on the National Institute of Mental Health Trichotillomania Impairment Scale (NIMH-TIS) (mean scores for clomipramine at baseline = 8.0, endpoint = 5.8; mean scores for placebo at baseline = 5.6, endpoint = 4.2; P value = NS).

 

Secondary outcomes

 
Responsiveness to treatment of comorbid symptoms of depression

 
Comparison 2.1: Clomipramine versus placebo

Ninan 2000 reported using the BDI to assess for depression but did not report the scores, nor were they available from the first author.

 
Tolerabilty of treatment

 
Comparison 2.1: Clomipramine versus placebo

In the Ninan 2000 trial of clomipramine versus placebo, three of 10 participants (30%) receiving clomipramine dropped out of the study because of significant drug-related adverse effects, although it is not stated which adverse effects caused participants to withdraw from the study. Common adverse effects in participants taking clomipramine were tremor (three of 10; 30%), sedation (two of 10; 20%), dry mouth (two of 10; 20%) and constipation (two of 10; 20%). The six participants who were taking placebo reported no adverse effects.

 
Responsiveness to treatment on quality of life measures

 
Comparison 2.1: Clomipramine versus placebo

No data are available on quality of life measures for Ninan 2000.

 

Comparison 3: TCA versus other TCA

 

Primary outcomes

Treatment response/reduction in symptom severity

 
Comparison 3.1: Clomipramine versus desipramine

The Swedo 1989 study provided evidence that clomipramine is effective when compared with desipramine; this evidence was based on two outcome measures: the NIMH-TIS and 'physician-rated clinical progress'. On the NIMH-TIS, the mean score at baseline was 6.8, at endpoint for clomipramine 4.2, and at endpoint for desipramine 6.2 (P value = 0.03). On Physician-rated Clinical Progress, the mean score at baseline was 10.0, at endpoint for clomipramine 4.7 and at endpoint for desipramine 8.7 (P value = 0.006). Evidence of the effectiveness of clomipramine compared with desipramine was not demonstrated on the final measure—the NIMH-TSS—although the direction of the effect was consistent with that reported for the other outcomes (mean score at baseline = 15.9, at endpoint for clomipramine = 10.6, at endpoint for desipramine = 14.4 (P value = 0.11)).

 

Secondary outcomes

 
Responsiveness to treatment of comorbid symptoms of depression

 
Comparison 3.1: Clomipramine versus desipramine

In the cross-over study by Swedo 1989, the NIMH global-assessment scale for depression was used to assess symptoms of depression. The study authors report that no participants scored in the range of clinical depression at the beginning of the study. The baseline depression score was 2.7 for the group, and endpoint scores were 2.2 and 1.5 for desipramine and clomipramine, respectively.

 
Tolerabilty of treatment

 
Comparison 3.1: Clomipramine versus desipramine

In the Swedo 1989 cross-over study comparing clomipramine versus desipramine, of the 13 participants, none withdrew because of adverse effects. The three common side effects affecting participants were constipation (five of 13 [38.5%] for clomipramine compared with six of 13 [46.2%] for desipramine), dry mouth (five of 13 [38.5%] for clomipramine and eight of 13 [61.5%] for desipramine) and tremor (seven of 13 [53.8%] for clomipramine and three of 13 [23.1%] for desipramine). The authors report that the P values were not significant for any of these results.

 
Responsiveness to treatment on quality of life measures

 
Comparison 3.1: Clomipramine versus desipramine

No data on quality of life measures are available for Swedo 1989.

 

Comparison 4: Glutamate modulators versus placebo

 

Primary outcomes

 
Treatment response/reduction in symptom severity

 
Comparison 4.1: NAC versus placebo

The study by Grant 2009 of N-acetylcysteine (NAC) versus placebo yielded strong evidence that NAC is effective when compared with placebo; this finding was based on all primary outcome measures. On the MGH-HPS, mean scores in the NAC group were 17.6 at baseline and 10.4 at study endpoint, and in the placebo group, mean scores were 16.7 at baseline and 16.0 at endpoint (P value < 0.001). The treatment effect was detected by nine weeks (P value = 0.002). Mean scores on the Psychiatric Institute Trichotillomania Scale (PITS) were 21.2 and 11.8 for the NAC group at baseline and endpoint, respectively, and 23.0 and 18.7 for the placebo group at baseline and endpoint, respectively (P value = 0.001). On the CGI-S, baseline and endpoint scores were 4.28 and 2.96, respectively, in the NAC group and 4.72 and 4.20, respectively, in the placebo group (P value = 0.03).

 

Secondary outcomes

 
Responsiveness to treatment of comorbid symptoms of depression

 
Comparison 4.1: NAC versus placebo

In the Grant 2009 study, which compared N-acetylcysteine versus placebo, depression rates were assessed using the HAM-D, and no clinical depression was detected in the group at baseline. Mean HAM-D scores for placebo were 3.68 and 3.32 at baseline and endpoint, respectively, and for NAC, 3.68 and 2.36 at baseline and endpoint, respectively. No evidence was available for N-acetylcysteine when compared with placebo in treating comorbid symptoms of depression (P value = 0.34).

 
Tolerabilty of treatment

 
Comparison 4.1: NAC versus placebo

In the Grant 2009 trial of N-acetylcysteine (NAC) versus placebo, participants receiving NAC (N = 25) did not experience any adverse effects. Of participants receiving placebo (N = 25), one complained of nausea, two of diarrhoea and one of cough. No participants withdrew from the study as the result of adverse effects.

 
Responsiveness to treatment on quality of life measures

 
Comparison 4.1: NAC versus placebo

For N-acetylcysteine (NAC) versus placebo, SDS and quality of life inventory scores were used to measure psychosocial functioning and quality of life. On the SDS, mean scores for the placebo group were 10.7 and 8.36 at baseline and endpoint, respectively, and for the NAC group, 9.0 and 5.60, respectively (P value = 0.11). On the QoL inventory, mean scores for the placebo group were 42.56 and 45.12 at baseline and endpoint, respectively, and for the NAC group, 45.16 and 50.24 at baseline and endpoint, respectively (P value = 0.25). Although functioning and quality of life improved to a greater numerical extent for those assigned to the NAC group, evidence was insufficient to suggest that NAC had an effect on these outcomes (Grant 2009).

 

Comparison 5: Antipsychotics versus placebo

 

Primary outcomes

 
Treatment response/reduction in symptom severity

 
Comparison 5.1: Olanzapine versus placebo

The study by Van Ameringen 2010 yielded strong evidence that olanzapine is effective when compared with placebo in improving trichotillomania severity on all primary outcome measures, with the exception of the MGH-HPS. On the CGI-I, mean scores in the olanzapine group were 3.38 and 1.69 in week two and at endpoint, respectively, and 3.41 and 3.41 in week two and at endpoint, respectively, in the placebo group (P value = 0.001). On the CGI-S, mean scores in the olanzapine group were 5.08 and 3.15 at baseline and endpoint, respectively, and 5.00 and 4.83 in the placebo group (P value < 0.001). On the Yale-Brown Obsessive Compulsive Scale (TTM-YBOCS), mean scores in the olanzapine group were 20.70 and 10.54 at baseline and endpoint, respectively, and 20.67 and 18.17 in the placebo group (P value < 0.01). Finally, on the MGH-HPS, mean scores in the olanzapine group were 15.46 and 8.38 at baseline and endpoint, respectively, and 16.58 and 13.25 at baseline and endpoint for placebo (P value = 0.30). The mean ± SD time to treatment response with olanzapine in this study was 8.2 ± 3.4 weeks.

 

Secondary outcomes

 
Responsiveness to treatment of comorbid symptoms of depression

 
Comparison 5.1: Olanzapine versus placebo

No evidence supported the effectiveness of olanzapine versus placebo in the treatment of comorbid symptoms of depression based on the Beck Depression Inventory, as reported in the paper (no scores given) (Van Ameringen 2010).

 
Tolerabilty of treatment

 
Comparison 5.1: Olanzapine versus placebo

In the Van Ameringen 2010 trial of olanzapine versus placebo, of participants receiving olanzapine (N = 13), none withdrew from the study as the result of adverse effects. The most common adverse effects were dry mouth (54% for olanzapine (N = 7) vs 0% for placebo; P value < 0.003), fatigue (54% for olanzapine (N = 7) vs 0% for placebo; P value < 0.003), increased appetite (46% for olanzapine (N = 6) vs 0% for placebo; P value < 0.007), headache (38% for olanzapine (N = 5) vs 33% for placebo (N = 4); P value = NS) and weight gain (38% for olanzapine (N = 5) vs 8% for placebo (N = 1); P value = NS). Four of the 25 participants experienced no adverse events.

 
Responsiveness to treatment on quality of life measures

 
Comparison 5.1: Olanzapine versus placebo

No strong evidence was obtained for the effectiveness of olanzapine versus placebo on measures of quality of life (SDS or Q-LES-Q) (Van Ameringen 2010).

 

Comparison 6: Opioid antagonists versus placebo

 

Primary outcomes

 
Treatment response/reduction in symptom severity

 
Comparison 6.1: Naltrexone versus placebo

The study by Christenson 1994 compared naltrexone versus placebo. This study was not published, and the study authors have not kept the raw data. They report evidence for naltrexone based on the NIMH Trichotillomania Severity Scale (P value = 0.02). The other outcome measures, however, did not yield evidence in favour of naltrexone: the NIMH TTM Impairment Scale (P value = 0.22), the NIMH Physician Rating Scale score (P value = 0.11), the number of hair-pulling episodes (P value = 0.16) and the estimated number of hairs pulled (P value = 0.35).

 

Secondary outcomes

 
Responsiveness to treatment of comorbid symptoms of depression

 
Comparison 6.1: Naltrexone versus placebo

For naltrexone versus placebo, no data measuring comorbid symptoms of depression were reported (Christenson 1991a).

 
Tolerabilty of treatment

 
Comparison 6.1: Naltrexone versus placebo

No data related to adverse effects were derived from the trial on naltrexone versus placebo (Christenson 1994).

 
Responsiveness to treatment on quality of life measures

 
Comparison 6.1: Naltrexone versus placebo

No data on quality of life measures were provided for the naltrexone trial (Christenson 1994).

 

7. Heterogeneity

Studies could not be meta-analysed; therefore differences between trials could not be assessed. However, these differences were addressed qualitatively in the Discussion section.

 

8. Subgroup analyses

Studies were insufficient to permit a subgroup analysis (< 10).

 

9. Sensitivity analyses

Studies were insufficient to allow a sensitivity analysis (< 10).

 

10. Publication bias

Studies were insufficient to permit detection of publication bias (< 10).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Summary of main results

Overall, a very small body of evidence is available on pharmacotherapy for TTM. Eight studies are included in this review, all published or presented between 1989 and 2010. For the SSRI class of antidepressants, three studies were identified (Christenson 1991a; Dougherty 2006; Streichenwein 1995), and for the TCA class of antidepressants, two RCTs (Swedo 1989; Ninan 2000) met inclusion criteria. The other three included studies examined a glutamate modulator (Grant 2009), an atypical antipsychotic (Van Ameringen 2010) and an opioid antagonist (Christenson 1994). The eight studies involved a total of 204 participants, with a mean sample size of 25.25 and a range of 13 to 50 participants. The included studies were not methodologically similar enough to be combined in a meta-analysis.

Individual trials of olanzapine (Van Ameringen 2010) and NAC (Grant 2009) have provided strong evidence for treatment effects in TTM. A single small trial of clomipramine (Swedo 1989) also provided evidence for a treatment effect in TTM, as measured by two of the three primary outcome measures.

 

Overall completeness and applicability of evidence

To the best of our knowledge, we have presented data from all published and unpublished trials that assessed the efficacy and tolerability of pharmacotherapeutic options for adult TTM. The trials included in this review are all applicable to our research question, as all seek to determine the efficacy of a particular medication in the treatment of adult TTM in an outpatient setting. However, the current evidence base of RCTs is not sufficient to demonstrate definitively superior efficacy or acceptability for any particular medication class for several reasons. The eight included studies cover five different medication classes; therefore evidence from individual medication classes is insufficient to allow conclusions to be drawn. A greater number of larger studies across a broad range of medication classes are needed before robust conclusions can be drawn. Nevertheless, evidence from single studies suggests that certain medications (clomipramine, olanzapine, NAC) may be efficacious (Grant 2009; Van Ameringen 2010).

Because of significant methodological heterogeneity among the included trials, it was not possible to conduct meta-analyses in this review. This methodological heterogeneity results in part from the use of a wide variety of TTM symptom scales, including some that have not been well validated or previously published. This is a matter of concern because evidence indicates that unpublished rating scales are more likely to favour the treatment group over the control group (Marshall 2000). Several possible reasons have been proposed for this, one of which is that post hoc 'adjustment' of unpublished scales by removing unfavourable items can skew the results in favour of the treatment group (Marshall 2000). In future studies, use of one or two validated symptom scales, such as the MGH-HPS, will enhance the possibility for the results to be combined and meta-analysed.

It will be important for future studies to include participants with psychiatric comorbidities, and to measure and report participant response to medication (e.g. depression and anxiety). The exclusion of participants with comorbid disorders means that study participants are likely not a good representation of clinical populations. Among the included studies in this review, three studies excluded participants with comorbid psychiatric disorders (Dougherty 2006; Swedo 1989; Van Ameringen 2010); one study excluded only participants with bipolar disorder or psychotic disorders (Grant 2009); and two studies did not specify comorbidities, and the information was not available (Christenson 1994; Ninan 2000). Inclusion of participants with other common comorbidities is important so that it can be determined, through subgroup analysis, whether the treatment effect of the medication on TTM is independent of the effect of the medication on comorbid disorders. Indeed, given the relative lack of evidence for the efficacy of any particular medication in treating trichotillomania, it would seem to make clinical sense to select medication on the basis of its effectiveness against comorbid disorders for which the evidence base is larger.

With the exception of clomipramine and desipramine, direct comparisons of the relative clinical effectiveness of medications in treating TTM are lacking. Multiple-treatment meta-analysis (MTM) might be a useful tool in future updates of this review in allowing comparison of three or more different interventions (potentially from different studies) in one meta-analysis. For MTM to be performed, the included studies would have to be similar in all ways other than the interventions being compared, which is not currently the case.

 

Quality of the evidence

The review included only eight studies of 204 participants, in total spanning five different medication classes (SSRIs, TCAs, antipsychotics, opioid-antagonists, glutamate modulators). The number of participants in the included studies was very small, ranging from 13 to 50, and four of the eight included studies had fewer than 20 participants. In addition to these small numbers, attrition rates of greater than 10% were seen in three of the eight trials (Dougherty 2006; Ninan 2000; Streichenwein 1995). In the Dougherty study, 37 participants were randomly assigned, but only 31 had their outcomes included in the final analysis, representing an attrition rate of 19%. In the Ninan study, 23 participants were randomly assigned and data from only 16 participants were analysed, for an attrition rate of 30%. In the Streichenwein study, 23 participants were randomly assigned with data from only 16 participants included in the final analysis, for an attrition rate of 30%. These trials did not employ intention-to-treat analyses, representing a high risk of attrition bias.

The use of different, unvalidated scales in some of the included studies diminishes the quality of evidence available from these studies. For example, two studies used a self-reported rating scale that relied on participants to count the number of hair-pulling episodes, as well as to rate the urgency and severity of hair-pulling (Christenson 1991a; Streichenwein 1995). Given that hair-pulling is often done without awareness, participants may be limited in their ability to keep track of their own hair-pulling.

Protocols for these trials were not publicly available, which limited our ability to determine whether there was reporting bias that might in turn have influenced outcomes.

Three of the trials included in this review employed a cross-over design (Christenson 1991a; Streichenwein 1995; Swedo 1989). Failure to include a washout period in the trial comparing clomipramine with desipramine (Swedo 1989) may have impacted the trial results because of the persistent effects of these agents on both TTM and comorbid conditions such as depression.

The limited number of studies and the limited number of participants, as well as the high attrition rates in many of the studies and the lack of intention-to-treat analyses, indicate that any conclusions about the pharmacotherapy of trichotillomania must be made with caution. The trials supporting the value of NAC and olanzapine in this disorder are high-quality trials, and they deserve replication (Grant 2009; Van Ameringen 2010).

 

Potential biases in the review process

We attempted to be as comprehensive as possible in the review process. As recommended for all Cochrane reviews, we conducted an extensive and comprehensive search of multiple electronic bibliographic databases to identify eligible trials for inclusion. We applied no language or publication restrictions in our search. We engaged directly with many of the trialists to obtain missing data or to ask for clarification when this was required. Potential bias in the conduct of our review was minimised by having two independent researchers extract data and assess the methodological quality of each study. This detailed process allowed a thorough assessment of trial conduct and an exploration of the possible biases that may be present in each trial. Despite all of the measures taken, it is possible that unpublished data have been reported that we did not find; this represents potential bias in the review process.

 

Agreements and disagreements with other studies or reviews

The methodology employed in this study differs from that employed in the meta-analysis of pharmacological trials conducted by Bloch 2007. Unlike in the present review, Bloch 2007 chose to perform a meta-analysis of the SSRI trials (Christenson 1991a; Dougherty 2006; Streichenwein 1995) and included a fourth trial Van Minnen 2003, which the present review excluded in view of its waiting-list control group (i.e. lack of a placebo group). In addition, Bloch 2007 included trials that used different rating scales from each other. The study authors did not find a statistically significant benefit of SSRIs over placebo (Bloch 2007). In the meta-analysis of the clomipramine trials, Bloch 2007 found that clomipramine demonstrated efficacy compared with placebo or active control conditions, and this difference was found to be statistically significant. In the present review, it was decided that the two clomipramine trials were not appropriate to combine in a meta-analysis, as one used a placebo group as a control and the other used desipramine as a control (Ninan 2000; Swedo 1989).

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

 

Implications for practice

No particular medication class definitively demonstrates efficacy in the treatment of trichotillomania. Preliminary evidence has suggested treatment effects of clomipramine, NAC and olanzapine, based on three individual trials, albeit all of which had very small sample sizes (Grant 2009; Swedo 1989; Van Ameringen 2010).

 
Implications for research

The existing evidence base of RCTs includes a mixture of parallel and cross-over trials, participants with a range of comorbid disorders and the use of unpublished rating scales. In addition, the existing trials have very small sample sizes, and the body of evidence is of low quality because of high attrition rates and lack of intention-to-treat analyses. In the future, trials on a variety of agents, of longer duration, with larger sample sizes and using validated rating instruments (such as the MGH-HPS) are needed. Given the preliminary evidence presented in three small trials of a glutamate modulator, a dopamine antagonist and a serotonergic TCA, further work on these three classes of drugs is indicated. (Grant 2009; Swedo 1989; Van Ameringen 2010).

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

We would like to thank the following principal investigators: Gary Christenson, Darin Dougherty, Jon Grant, Suzan Streichenwein, Susan Swedo and Michael Van Ameringen, for the clarification they kindly provided on various aspects of their trials.

CRG Funding Acknowledgement:
The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Depression, Anxiety and Neurosis Group. 

Disclaimer:
The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
Download statistical data

 
Comparison 1. Sertraline versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Massachusetts Hair-pulling scale1Mean Difference (IV, Fixed, 95% CI)Subtotals only

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Appendix 1. MEDLINE, EMBASE, PsycINFO Searches (to 2013)

MEDLINE (1966-2013) - via PubMed was searched using the following terms:
(randomised controlled trial [pt] OR controlled clinical trial [pt] OR randomised controlled trials [mh] OR random allocation [mh] OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR ("latin square" [tw]) OR placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow-up studies [mh] OR prospective studies [mh] OR cross-over studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animal [mh] NOT human [mh]) AND AND (Trichotillomania [mh] OR trichotillomania [tw] OR TTM [tw])

EMBASE (1980-2013) was searched using the following terms:
(random* OR "placebo":de OR control*) AND (trichotillomania:de)

PsycINFO (1970-2013) was searched using the following terms:
("randomisation" OR "randomisation" OR "controlled") AND ("trichotillomania")

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

Rachel Rothbart and Taryn Amos conducted the review and wrote a first draft; Dan Stein coordinated the review and assisted with writing. Nandi Siegfried provided teaching and guidance to the principal author based on her extensive experience conducting Cochrane reviews, acted as arbiter in eligibility and extraction decisions and assisted with analysis and writing. Jonathan Ipser contributed towards the methodology section of the protocol and provided feedback on the review. Naomi Fineberg and Sam Chamberlain provided feedback on subsequent modifications of the protocol and review.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

The MRC Anxiety and Stress Disorders Research Unit has received funding from most pharmaceutical companies involved with psychiatry in South Africa.

Rachel Rothbart declares no conflicts of interest.

Taryn Amos declares no conflicts of interest, outside of her employment by the Medical Research Council of South Africa.

Samuel Chamberlain has received consultancy honoraria from Cambridge Cognition, Shire, Lilly and P1Vital.

Naomi Fineberg has received research grants, consultancy fees and/or honoraria from Lundbeck, GlaxoSmithKline, Janssen, Cephalon, Wyeth, AstraZeneca, Jazz Pharmaceuticals and Servier. She has presented data from trials on behalf of sponsoring companies.

Jonathan Ipser declares no conflicts of interest.

Dan Stein has received research grants and/or honoraria from AstraZenica, Eli Lilly, GlaxiSmithKline, Lundbeck, Orion, Pfrizer, Pharmacia, Roche, Servier, Solvay, Sumitomo and Wyeth.

Nandi Siegfried declares no conflicts of interest.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Internal sources

  • MRC Unit on Anxiety Disorders, South Africa.

 

External sources

  • University of Cape Town, Cape Town, South Africa.

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

  • Selection of studies and data extraction were performed by RR and TA, not by the original authors assigned to these tasks (JI and LH).

  • Online forms were not used for recording data; instead data extraction sheets were created for manual data extraction.

  • Risk of bias was assessed by RR and TA, not by the original authors assigned to these tasks (JI and LH). The CCDAN Quality Rating Scale was not used, as the 'Risk of bias' tool has made it obsolete.

  • One of the objectives stated in the protocol was to identify clinical and methodological factors that predict response to medication. This was not done because of the small number of included studies and the lack of meta-analysis, but it remains possible in future updates of the review.

  • Types of participants: We planned to tabulate age, gender and race to address the question of their possible impact on the effects of medication; however, this was not done.

  • Data collection and analysis section: The SRS 4.0 online systematic review system TrialStat was not used for trial selection and data extraction purposes. Data extraction was instead performed manually onto data extraction sheets (paper copies).

  • Descriptive information for each trial was not made freely available in the ESRNexus electronic database (http://www.esrnexus.com/), as the TrialStat program was not used; therefore the stipulation of the TrialStat FRIENDS program that this be done no longer applied.

  • Unit of analysis issues: Cross-over trials that lacked a washout period were included if the drugs compared were of the same class and had similar properties (this was stated in the 'Unit of analysis issues' section).

  • Mood stabilisers (e.g. lithium) and nutraceuticals (e.g. NAC, inositol) were added as categories under 'Types of interventions' in the 'Methods' section.

  • We added multi-arm analyses and multiple treatment meta-analyses as methodological options to maximise the use of all data.

  • Additional sensitivity analyses were included under 'Subgroup analysis and investigation of heterogeneity' in 'Methods', namely, exclusion of results based on last observation carried forward (LOCF) or observed cases (OC), exclusion of cross-over trials, exclusion of cluster-randomised trials and varying of intracluster correlation coefficients (ICCs) in cluster-randomised trials.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to ongoing studies
  20. Additional references
Christenson 1991a {published data only}
  • Christenson GA, Mackenzie TB, Mitchell JE, Callies AL. A placebo-controlled, double-blind crossover study of fluoxetine in trichotillomania. American Journal of Psychiatry 1991;148(11):1566-71.
Christenson 1994 {unpublished data only}
  • Christenson GA, Crow SJ, Mackenzie TB, Crosby RD, Mitchell JE. A placebo controlled double-blind study of naltrexone for trichotillomania [abstract NR597]. American Psychiatric Assocation Annual Meeting. Philadelphia: APA, 1994:212.
Dougherty 2006 {published data only}
  • Dougherty DD, Loh R, Jenike MA, Keuthen NJ. Single modality versus dual modality treatment for trichotillomania: sertraline, behavioral therapy, or both?. Journal of Clinical Psychiatry 2006;67(7):1086-92.
Grant 2009 {published data only}
  • Grant JE, Odlaug BL, Kim SW. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Archives of General Psychiatry 2009;66(7):756-63.
Ninan 2000 {published data only}
  • Ninan PT, Rothbaum BO, Marsteller FA, Knight BT, Eccard MA. A placebo-controlled trial of cognitive-behavioral therapy and clomipramine in trichotillomania. Journal of Clinical Psychiatry 2000;61(1):47-50.
Streichenwein 1995 {published data only}
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Swedo 1989 {published data only}
Van Ameringen 2010 {published data only}
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References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to ongoing studies
  20. Additional references
Bloch 2013 {published data only}
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  • 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. Journal of the American Academy of Child and Adolescent Psychiatry March 2013;52(3):231-40.
Chamberlain 2010 {published data only}
Riley 1993 {published data only}
Van Minnen 2003 {published data only}
  • Van Minnen A, Hoogduin KAL, Keijsers GPJ, Hellenbrand I, Hendriks GJ. Treatment of trichotillomania with behavioral therapy or fluoxetine. Archives of General Psychiatry 2003;60:517-22.

References to ongoing studies

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to ongoing studies
  20. Additional references
Grant 2012 {published data only}
  • Grant JE. A double-blind, placebo-controlled study of naltrexone in trichotillomania. ClinicalTrials.gov/ct2/show/NCT00775229 (accessed 6 August 2013).
Grant 2013 {published data only}
  • Grant JE. A double-blind, placebo-controlled study of inositol in trichotillomania. ClinicalTrials.gov/ct2/show/NCT01875445 (accessed 18 August 2013).

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  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to ongoing studies
  20. Additional references
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