Pharmacotherapy for anxiety disorders and comorbid alcohol dependency
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
1) To provide an estimate of the overall effects of the medication in improving treatment response and reducing symptom severity in the treatment of anxiety disorders in patients with comorbid alcohol dependence.
2) To determine whether particular medications are more effective and tolerable than others in the treatment of this population group.
3) To determine whether the efficacy and tolerability of medications in treating anxiety disorders is specific to particular anxiety disorders.
4) To identify which factors (clinical, methodological) predict response to pharmacotherapy.
Background
Description of the condition
Anxiety disorders are highly prevalent and are associated with high social, personal and economic costs. This class of disorders includes generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD), panic disorder (PD), posttraumatic stress disorder (PTSD), social anxiety disorder (SAD) and specific phobia (SP). Though differing in specific symptomatic profiles, the anxiety disorders are characterised by a state of chronic physiological hyperarousal to fear‐inducing contexts (such as those involving social interaction in the case of SAD).
Anxiety disorders frequently co‐occur with alcohol dependence, which is defined in the latest edition of the Diagnostic and Statistical Manual (DSM‐IV‐TR) as the presence of three of the following criteria anytime over a 12‐month period: evidence of tolerance to alcohol; symptoms of withdrawal following termination of alcohol use; consumption of increasing alcoholic beverages in larger amounts or over a longer time span than anticipated; unsuccessful attempts to reduce alcohol intake; the spending of large amounts of time acquiring alcohol; reduction or quitting of social, occupational or recreational activities due to drinking; and continued drinking despite knowledge that this leads to persistent or recurrent physical or psychological problems (APA 2000).
The diagnosis of alcohol dependence is approximately 2 to 4 times more likely for individuals diagnosed with a range of anxiety disorders (Regier 1990, Kessler 1997, Hashin 2007). A nationally representative survey in the US found lifetime prevalence rates of co‐occurring alcohol dependence and anxiety disorders to be as high as 35.8% for men and 60.7% for women (Kessler 1997). In contrast, the European Study of the Epidemiology of Mental Disorders reported a prevalence rate of only 0.1% for comorbidity of these diagnoses over a 12 month period across 6 European countries (Alonso 2004). Nevertheless, the co‐occurence of these disorders have been associated with more severe symptoms, and a corresponding increase in the utilisation of mental health services (Kessler 1996). There is also some epidemiological evidence of a poorer prognosis for patients with these disorders in alcoholism treatment programs, as well as increased rates of relapse (Driessen 2001, Kushner 2005).
The nature of the relationship between alcohol dependence and anxiety disorders have been articulated in a number of theoretical models. Those which assign primacy to the anxiety disorders typically ascribe to the notion that alcohol is abused to help cope with anxiety‐provoking situations. Such models include the Tension Reduction Theory (TRT)(Kushner 1990) and the Self‐Medication Hypothesis (SMH) (Khantzian 1985), and may be particularly relevant for anxiety disorders which typically precede onset of dependence, such as SAD and agoraphobia (Kushner 1990, Brady 1993). Indeed, evidence of a causal interaction between anxiety disorder symptoms and alcohol dependence includes a possible dose‐response relationship between the severity of social phobia symptoms and degree of abusive drinking (Morris 2005), as well as the finding that early treatment of anxiety disorder symptoms reduced subsequent alcohol abuse (Kendall 2004)
Description of the intervention
Certain forms of psychotherapy, such as cognitive behaviour therapy (CBT), have been recommended in clinical practice guidelines as a first line treatments for anxiety disorders (CPA 2006, NICE 2005). Behavioural programmes designed for treating alcohol dependence may not be effective in reducing anxiety disorder symptoms, as discovered by investigators in a controlled trial of CBT for comorbid alcoholism and panic disorder (Bowen 2000). Indeed, the effectiveness of CBT for treating anxiety disorders might be limited by comorbid alcohol dependency, with alcohol consumption likely to impair desensitisation to stressors and modification of maladaptive cognitions, core components of CBT (Morris 2005). SMH would also predict increasing rates of relapse following the application of stress‐inducing treatment modalities, such as exposure therapy. This is consistent with the failure to detect reduced relapse rates in the majority of randomised controlled trials of alcoholism treatment interventions which have incorporated CBT for anxiety disorders (Bowen 2000, Randall 2001, Schade 2005).
The possible limitations of psychotherapy for anxiety disorder patients with comorbid alcohol dependence, and the increasing elucidation of the biological substrates of alcohol dependency suggests that pharmacotherapy should be considered as a treatment option. Alterations in the functioning of the GABA neurotransmitter system have been identified as fundamental to alcohol response, dependency, vulnerability and pharmacotherapy (Krystal 2006). The activation of GABA receptors and inhibition of the sympathetic system (with corresponding inhibition of the noradrenergic pathway) have been implicated in the stress‐reducing effects observed following alcohol consumption. Notably, alcohol dependence and withdrawal is associated with a subsequent reduction in GABA activity (Krystal 2006), potentially explaining how the initial anxiolytic effects of imbibing alcohol give way to increasing levels of anxiety with alcohol dependence (Kushner 1990). GABAenergic medications which have demonstrated some efficacy in treating anxiety disorders, such as the benzodiazepines, and the anticonvulsant pregabalin (Feltner 2003; Rickels 2005; Pohl 2005; Pande 2004) might be expected to be effective in patients with comorbid alcohol disorders. Benzodiazepines are generally not recommended, however, given the risk of dependency, and the finding of prolonged withdrawal symptoms and increased alcohol use following a randomised controlled detoxification treatment with lorazepam (Malcolm 2002).
The selective serotonin reuptake inhibitors (SSRIs) are regarded as first‐line medication agents in treating anxiety disorders (BAP 2005). The evidence for the efficacy of SSRIs in reducing alcohol consumption is less clear‐cut, with some evidence that SSRIs may produce favourable outcomes when treating patients with less severe alcohol dependence (Pettinati 2000), but may actually reduce the efficacy of CBT treatment for severe alcohol dependence (Kranzler 1996). A controlled trial of the addition of mirtazapine, a noradrenergic and specific serotonergic antidepressant, to a CBT alcohol dependence/abuse detoxification protocol, found a significant reduction in social anxiety symptoms, suggesting the usefulness of medication targeting neurotransmitter systems implicated in both disorders (Liappas 2003). Concerns surrounding the side‐effects of naltrexone, a FDA approved medication for relapse prevention, indicate that it might not be suitable for the treatment of comorbid anxiety disorders and alcohol dependence, despite the finding that this medication reduced the severity of PTSD symptoms in a number of open‐label trials (Bills 1993, Lubin 2002)
The possibility that alcohol dependence and anxiety disorders may reinforce one another following onset suggests that treatment strategies which target the symptoms of both forms of psychopathology might be effective. Evidence of treatment efficacy from a RCT combining CBT with sertraline in treating PTSD and alcohol dependence (Back 2006) also supports the potential usefulness of so‐called combination therapies. Indeed, most treatment guidelines for people with co‐occurring anxiety and substance abuse disorders recommend integrated treatment interventions, though there is little evidence from randomised controlled trials that this strategy is more effective than treating either disorder individually (Watkins 2005, Schade 2003).
Why it is important to do this review
There are a number of shortcomings in the literature on the treatment of anxiety disorders in populations diagnosed with comorbid alcohol dependence. A general paucity of evidence exists for recommendations for treating affective or anxiety disorders that are comorbid with substance use disorders (Watkins 2005). Clinical trials of medication for treating anxiety disorders also frequently exclude patients with comorbid alcohol dependency, limiting the generalisability of their findings. The small samples employed by dual‐diagnosis medication trials may also have prevented the detection of significant differences in the efficacy of treatments for anxiety disorders. A systematic review and meta‐analysis, employing the methodology of the Cochrane Collaboration, would help to quantify the extent of these shortcomings, and through the synthesis of trial data, assist in addressing other questions of interest in the treatment of anxiety disorders with comorbid alcohol dependence. These include (a) the relative efficacy of different agents in treating particular anxiety disorders, (b) the effectiveness of the same agent across anxiety disorders, and (c) whether clinical differences, such as gender, predict response to treatment.
Objectives
1) To provide an estimate of the overall effects of the medication in improving treatment response and reducing symptom severity in the treatment of anxiety disorders in patients with comorbid alcohol dependence.
2) To determine whether particular medications are more effective and tolerable than others in the treatment of this population group.
3) To determine whether the efficacy and tolerability of medications in treating anxiety disorders is specific to particular anxiety disorders.
4) To identify which factors (clinical, methodological) predict response to pharmacotherapy.
Methods
Criteria for considering studies for this review
Types of studies
All true randomised controlled trials of pharmacotherapy for treating anxiety disorders with comorbid alcohol dependence. Trials in which the allocation sequence is generated via a quasi‐random procedure (such as determining group allocation by day of the week or alternation) will not be included. Group‐based treatments will only be included on the condition that they employed a cluster randomisation design. Although the absence of treatment outcome data will exclude RCTs from the meta‐analyses, they will still be eligible for inclusion as part of the narrative review.
Types of participants
All patients diagnosed with alcohol dependence and an anxiety disorder according to DSM‐III (APA 1980), DSM‐IV (APA 1994) and DSM‐IV‐TR (APA 2000) criteria will be included. Participants diagnosed with additional comorbid psychiatric diagnoses (excluding other secondary anxiety disorders) will not be included. The presence of physical disabilities will not qualify as an exclusion criteria, with the exception of traumatic brain injury in RCTs of PTSD (due to difficulties in distinguishing between the symptoms of PTSD and TBI). No age restrictions will be imposed. Participants will be limited to those diagnosed with alcohol dependence rather than alcohol abuse, given the consistent finding of a stronger relationship between dependence and anxiety disorders (Kessler 1997).
Alcohol withdrawal may result in a short‐term increase in anxiety symptoms, with evidence that these symptoms stabilise within 4 to 8 weeks of the onset of abstinence (Schuckit 1988; Driessen 2001). Therefore, studies that diagnose anxiety disorders with a symptom profile similar to that observed during withdrawal (i.e.. generalised anxiety disorder, panic disorder) within four weeks after the discontinuation of alcohol consumption will not be included in the meta‐analysis. Both trials targeting relapse prevention as well as the treatment of ongoing alcohol dependence will be included in the review.
Types of interventions
Interventions
In recognition of the possibility of differential effects for different medications, all of the comparisons will be stratified by medication class. Individual agents will be classified as either selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase inhibitors (RIMAs), benzodiazepines or "Other medication". In addition, all comparisons will be stratified by the specific anxiety disorder (GAD, OCD, PD, PTSD, SAD, or SP) targeted.
As it is anticipated that the majority of treatment studies targeting anxiety disorders in patients with comorbid alcohol dependence will employ concurrent behavioural modification programmes to treat alcohol dependence, the presence of such strategies will not serve as an exclusion criteria.
Control conditions
Control conditions will include placebo, treatment as usual and other medication agents.
Main comparisons
The following interventions will be compared:
1) medication versus placebo
2) medication versus treatment as usual
3) medication versus other medication agents
4) combination of medication and concurrent psychotherapy versus pharmacotherapy alone
Types of outcome measures
Primary outcomes
Treatment response (responders versus non‐responders) will be determined from the Clinical Global Impressions scale ‐ Improvement item (CGI‐I) (or closely related measure), a widely used global outcome measure (Guy 1976). Responders are defined on the CGI‐I as those with a score of 1="very much" or 2="much" improved. The reduction of symptom severity will be determined from a variety of validated continuous outcome measures, such as the Liebowitz Social Anxiety Scale (LSAS) (Liebowitz 1987) and the Clinician Administered PTSD Scale (CAPS) (Blake 1990).
Secondary outcomes
1) Scores on rating scales for disorders other than the primary anxiety disorder, including:
a) Abstinence and reduction of alcohol use. This will be assessed using the component subscales of standardised instruments such as the Timeline Followback scale (TLFB)(Sobell 1992). In trials which do not use such an instrument, these outcomes will be assessed in terms of the operational definitions employed by study authors.
b) Reduction of comorbid symptoms of depression. This will be assessed using scales such as the Beck Depression Inventory (BDI) (Beck 1961), the Hamilton Depression scale (HAM‐D) (Hamilton 1959), and the Montgomery‐Asberg Depression Rating Scale (MADRS) (Montgomery 1979).
2) The effectiveness of medication will be assessed with measures of:
a) Quality of life measures, such as the SF‐36 Health Survey (Ware 1992)
b) Measures of functional disability, such as the Sheehan Disability Scale (SDS), which includes subscales to assess work, social and family related impairment (Sheehan 1996).
3) Finally, the acceptability of medication will be determined by:
a) The total proportion of participants who withdrew from the RCTs due to treatment emergent adverse events. This will be assessed as a surrogate measure of medication acceptability, in the absence of other more direct indicators of acceptability.
b) The most common drug‐related adverse events for both the included and excluded studies (defined as those occurring in at least 10% of the participants given medication) , as well as significant differences in the rate of occurrence of drug‐related adverse events between medication and control groups. This will be described as part of the narrative review.
Search methods for identification of studies
Electronic searches
a) The specialised Controlled Trials Registers of the Cochrane Collaboration Depression, Anxiety and Neurosis review group and the Drugs and Alcohol review group will be searched.
b) The Cochrane Central Register of Controlled Trials [CENTRAL](The Cochrane Library Issue 4 2007) will be searched.
c) Additional searches will be carried out on MEDLINE via PubMed (January 1980 to June 2008), through PsycINFO (1970 to June 2008), and EMBASE (1966 to June 2008), and through the Alcohol and Alcohol Problems Science Database (1979 to June 2008) (http://etoh.niaaa.nih.gov).
The complete MEDLINE search query, as derived from the search strategy developed by Robinson and Dickersin (Robinson 2002) is provided in Appendix 1.
d) Ongoing trials will be located using the metaRegister of Controlled Trials database (mRCT)(http://www.controlled‐trials.com), as well as the National Institute of Health's Computer Retrieval of Information on Scientific Projects [CRISP] service (1972‐2007). Additional trials will be accessed via the search portal of the WHO International Clinical Trials Registry Platform (http://www.who.int/trialsearch/). The WHO database includes the clinicaltrials.gov, Australian New Zealand Clinical Trials Registry and the ISRCTN databases. The search terms '"alcohol" AND "anxiety" will be entered into the search interface for these databases. Additional trials will be identified by browsing trial records listed on the clinicaltrials.gov website, under the following categories: "anxiety disorders", "alcohol‐related disorders" and "alcoholism".
Searching other resources
1) Reference Lists
The bibliographies of all identified trials will be scanned for additional studies.
2) Correspondence
a) Published and unpublished trials will also be obtained from key researchers, as identified by the frequency with which they are cited in the bibliographies of RCTs and open‐label studies.
b) Pharmaceutical companies will also be contacted. They will be identified through the source of funding cited in published RCTs, as well as the companies with which the authors are affiliated
Data collection and analysis
Selection of studies
RCTs identified from the search will be independently assessed for inclusion by two raters, based on information included in the abstract and/or method section of the trial report. The raters will also independently collate the data listed under "Data extraction and management" from RCTs that they both regard as satisfying the inclusion criteria specified in the "Criteria for considering studies" section. Studies for which additional information is required in order to determine their suitability for inclusion in the review will be listed in the "Studies awaiting assessment" table in the Review Manager (RevMan) software, pending the availability of this information. Any disagreements in the independent trial assessment and data collation procedures will be resolved by discussion.
Data extraction and management
Spreadsheet forms will be designed for the purpose of recording descriptive information, summary statistics of the outcome measures, the quality scale ratings, and associated commentary. Once these data have been entered, they will be exported to the Review Manager (RevMan) software, which will be used to conduct the meta‐analysis. Where information is missing, the reviewers will contact investigators by email in an attempt to obtain this information.
The following information will be collated from each trial:
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 randomised to the treatment and control groups, the number of total drop‐outs per group as well as the number that dropped out due to adverse effects, the dose of medication and the period over which it was administered, and the agents used for treating the anxiety disorder and alcohol dependence. Details of any concurrent psychotherapy will also be recorded.
3) Characteristics of trial methodology, including the diagnostic (e.g.. DSM‐IV (APA 1994)) and exclusionary criteria employed, the screening instrument used (e.g.. the Structured Clinical Interview for DSM‐IV (SCID) (Spitzer 1996)) for both 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, the number of centres involved, the period of abstinence in relapse‐prevention trials and the trial's total score on the CCDAN quality rating scale.
4) Characteristics of participants, including gender distribution and mean and range of ages, mean length of time since diagnosis with the anxiety disorder and alcohol dependence, whether they 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 the anxiety disorder and alcohol dependence, as assessed by the trial's primary outcome measure 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 will be 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, will also be recorded.
6) Quality assessment, including the number of randomised participants who were not included in the analysis (lost to follow‐up (LTF)), whether blinding occurred for the assessor/s, patients, or those who administered medication, as well as whether the allocation of medication was randomised and the allocation sequence was concealed (the methods used in implementing these respective bias reduction measures will also be documented).
Assessment of risk of bias in included studies
The methodological quality of the trials will be assessed independently by two review authors. Risk of bias will be assessed using the Risk of bias approach recommended in the Cochrane Handbook. This tool addresses six domains ‐ sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other issues. A description of what was reported to have happened in the study will be given for each domain, and a judgement relating to the risk of bias will be assigned (low risk, unclear risk and high risk). The possibility of attrition bias due to non‐equivalent drop‐out rates in the medication and comparison groups will also be assessed as part of the risk of bias approach. Any disagreements about methodological quality will be resolved by consultation with a third review author (DS).
Measures of treatment effect
Categorical data
Relative risk of response to treatment and number needed to treat (NNT) will be calculated for the dichotomous primary outcome of interest (CGI‐I or related measure). Relative risk will be used instead of odds ratios, as odd ratios are less easily interpreted. Odds ratios also tend to overestimate the size of the treatment effect when confused with relative risks. This is especially the case when the occurrence of the outcome of interest is common (as anticipated in this review, with an expected response greater than 20%) (Deeks 2005). NNT is defined as the inverse of the absolute risk difference due to the medication intervention. In this review it will be used to indicate the number of patients who require treatment with medication, relative to a control, before a single additional patient in the medication group responds to treatment. The number of patients who relapse in relapse prevention studies will be calculated for categorical measures of treatment response for both the anxiety disorder and alcohol use.
Continuous data
Weighted mean differences (WMD) will be calculated for continuous summary data derived from the same scale. For cases in which a range of scales are employed, such as in the assessment of symptom severity on the LSAS and CAPS, as well as in the assessment of comorbid depression on the MADRS and HAM‐D, the standardised mean difference (SMD) will be determined for each outcome. This method of analysis standardises the differences between the means of the treatment and control groups in terms of the variability observed in the trial.
Unit of analysis issues
Studies with multiple treatment groups
In trials comparing the efficacy of multiple medications in treating anxiety disorders, placebo‐medication outcome comparisons will be restricted to one of the medications. Data from only one medication group will be used so as to avoid possible bias through multiple comparisons with the same placebo group. Separate head‐to‐head primary outcome comparisons of the respective agents will be conducted for trials comparing multiple medications.
In the case of data from trials employing multiple fixed doses of medication, the bias introduced through comparing the summary statistics for multiple groups against the same placebo control will be avoided by pooling the means and standard deviations across all of the treatment arms as a function of the number of participants in each arm (ensuring that the influence of each arm is proportional to its sample size). The pooling of outcome data will be restricted to those arms that employ at least the minimum dose recommended by clinical guidelines, in order to reduce the influence of data from arms that employ doses unlikely to have a clinical effect.
Cross‐over trials
Cross‐over trials will only be included in the calculation of the outcomes of interest when it is (a) possible to extract medication and placebo/comparator data from the first treatment period, or (b) when the inclusion of data from both treatment periods is justified through a wash‐out period of sufficient duration as to minimise the risk of carry‐over effects. An adequate wash‐out period is defined in accordance with clinical practice as at least two weeks for all agents with the exception of fluoxetine, for which a minimum wash‐out period of four weeks will be required, given the long plasma half‐life of this agent. For trials in which the washout period is regarded as adequate, data from both periods will only be included when it is possible to determine the standard error of the mean difference in response between groups (Elbourne 2002). The summary statistics required to derive the standard error of interest will be obtained from the trial report, or for trials for which this information is missing, will be imputed through averaging the relevant statistic from other included crossover trials with comparable control conditions.
Dealing with missing data
All analyses of dichotomous data will be intention‐to‐treat (ITT). This will be achieved by including the total number of participants randomised to the different comparison groups as the denominator in comparisons of treatment response. Only data from trials which provide information on the original group size (prior to drop‐outs) will be included in the analyses of treatment response. Preference will be given to the inclusion of summary statistics for continuous outcome measures derived from mixed effects models, followed by last observation carried forward (LOCF) and observed cases (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
Heterogeneity of treatment response and symptom severity will be assessed visually from the forest plot of relative risk. This will help determine whether the differences between the results of trials were greater than would be expected by chance alone. Heterogeneity will also be assessed by means of the chi‐square test of heterogeneity. If the chi‐square test has a p‐value of less than 0.10, this will be interpreted as evidence of heterogeneity, given the low power of the chi‐square statistic when the number of trials is small (Deeks 2005).
In addition, the I‐square heterogeneity statistic reported by RevMan will be used to determine differences in effect size across trials that can not be explained by chance alone (Higgins 2003). An I‐square statistic of greater than 30% and 50% will arbitrarily be regarded as indicative of moderate and severe heterogeneity, respectively. Differences on continuous measures in medication efficacy between these subgroups will be assessed by means of Deeks' stratified test of heterogeneity (Deeks 2001). This method subtracts the sum of the chi‐square statistics available for each of the subgroups in the study from the chi‐statistic available for all the trials, to provide a measure (Qb) of heterogeneity between groups. Differences in treatment response on the CGI‐I will be determined by whether the confidence intervals for the effect sizes of the subgroups overlap. This method was chosen in preference to the stratified test, due to inaccuracies in the calculation in RevMan of the chi‐square statistic for dichotomous measures (Deeks 2005).
In recognition of the possibility of differential effects for different medications, all of the outcome comparisons (excluding subgroup and sensitivity analyses) will be stratified by the agent employed. In addition, the same comparisons will also be stratified by the specific anxiety disorder targeted.
Assessment of reporting biases
Publication is not necessarily related to study quality and indeed publication may imply certain biases (Dickersin 1992; Song 2000). Small‐sample effects (including publication bias) will be determined by visual inspection of a funnel plot of treatment response.
Data synthesis
Categorical and continuous treatment effects will be obtained 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 effects model takes only within‐study variation into account). The outcomes will be expressed in terms of an average effect size for each subgroup, as well as by means of 95% confidence intervals. In trials that incorporate a follow‐up phase, data from the final assessment point will be combined for all outcome measures. Comparisons of global treatment response and reduction of symptom severity on primary and secondary outcomes will be stratified by study design (long‐term maintenance studies (>14 weeks), relapse‐prevention trials or acute treatment interventions).
Subgroup analysis and investigation of heterogeneity
Subgroup analyses will be undertaken in order to assess the degree to which clinical and methodological differences between trials might have systematically influenced differences observed in the primary treatment outcomes.
The trials are to be grouped according to the following clinical sources of heterogeneity (number of trials permitting):
1) The gender of participants. Primary outcomes will be compared between trials which consist predominantly of men or women (defined arbitrarily as constituting greater than 70% of the total sample). Evidence that men and women metabolise alcohol differently, that anxiety disorders precede alcohol dependence significantly more frequently in women than men (Kessler 1997) and that men have different expectancies regarding the effects of alcohol that women (Morris 2005) suggests that gender might effect treatment outcome.
2) Whether or not the sample included patients diagnosed with major depression. Such an analysis might assist in determining the extent to which the efficacy of a medication agent in treating PTSD is independent of its ability to reduce symptoms of depression, an important consideration given the classification of many of these medications as antidepressants.
In addition, the following criteria will be used to assess the extent of methodological sources of heterogeneity:
1) The involvement of participants from a single centre or multiple centres. Single centre trials are more likely to be associated with lower sample size but less variability in clinician ratings.
2) Whether or not trials were industry funded. In general, published trials which are sponsored by pharmaceutical companies appear more likely to report positive findings than trials which are not supported by for‐profit companies (Als‐Nielsen 2003; Baker 2003).
3) The relative order of implementing treatment for anxiety disorders and alcohol dependence. Comparisons will be conducted between treatment effects for trials will employ treatment for the anxiety disorder first, alcohol dependence first, or which implement treatment for both disorders simultaneously.
4) Whether or not psychotherapy was implemented concurrently with pharmacotherapy.
Sensitivity analysis
Sensitivity analyses determine the robustness of the reviewer's conclusion to methodological assumptions made in conducting the meta‐analysis. A sensitivity analysis will be conducted to determine whether treatment response varies as a function of 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 will accordingly only be performed if the majority of trials report a control group event rate higher than 50%.
A "worst case/best case" analysis will also be conducted to determine the influence of the exclusion of participants who were lost to follow up (LTF) on the findings of treatment efficacy (Deeks 2005). In the worst case, all the missing data for the treatment group were recorded as non‐responders, whereas in the best case, all missing data in the control group were treated as non‐responders. Should the 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.
