Objectives
The general aim is to determine whether topiramate is at least as effective as NST in tobacco cessation at 1-year follow-up in patients with depression. The specific aims are to determine the factors that predict a good response to topiramate treatment and the possible differences in effectiveness in relation to gender.
Design
This is a controlled trial with a random allocation of patients into two alternative branches (see Figure 1):
1. Tobacco cessation standard treatment with NST (control group) and
2. Tobacco cessation treatment with topiramate (intervention group).
The evaluation of the treatment outcomes will be performed at patient level and they will be assessed individually.
Setting and study sample
Patients will be recruited from any of the 29 primary health care centres in the city of Zaragoza (Aragonese Health Service), Spain. Patients will be recruited by doctors working in these primary care centres until the required sample is completed, without a quota of patients assigned for every centre.
Patients considered for inclusion are those aged 18–65 years, able to understand and read Spanish, who fulfil criteria for major depression (DSM-IV criteria), with scores on the Zung Self-Rating Depression Scale < 60 [22] (implying minimal to mild depression), who smoke more than 20 cigarettes/day, fulfil preparation state of change according to Prochaska & DiClemente [23], voluntarily ask for a tobacco cessation therapy, and sign informed consent. Those excluded will be patients with active psychosis and/or treatment with antipsychotic drugs, alcohol or drug abuse, and pregnancy or lactation.
Randomisation, allocation and masking of study groups
Each patient will be allocated to either the intervention or the control group using a computer-generated random number sequence. The allocation will be carried out by an independent person, belonging to REDIAPP (Research Network on Preventative Activities and Health Promotion), who is not involved in the study. The method used to implement the random allocation sequence will be a central telephone. The sequence will be concealed until interventions are assigned. Patients agree to participate before the random allocation and without knowing which treatment they will be allocated to. Pharmacological treatment will be administered by a psychiatrist (JGC). Study personnel conducting psychological intervention and assessments (NS, AM, AC) will be masked to participants' treatment conditions.
Intervention
Psychological intervention in both groups
A multi-component programme for tobacco cessation is offered to all of the patients in the study. This is made up of pharmacological therapy + group cognitive-behavioural therapy. The group is made up of 7–12 patients with depression and tobacco dependence, and is led by 2 therapists (a psychologist and a family doctor) trained in group therapy and tobacco cessation. Each session lasts 90 min., and the structure of every session and the contents are manualised and based on the standard programmes of this type [19]. It consists of 16 follow-up sessions: D (cessation day) -1, D +1, weeks 1, 2, 3, 4, 6, 8, 10 and 13, and months 4, 5, 6, 8, 10 and 12. Patients will be offered a phone number on which study personnel can solve problems and answer queries in relation to psychological (NS, AM) or pharmacological treatment (JGC).
Pharmacological intervention
Intervention group
In this group of patients, topiramate at doses used for the treatment of addictions (100–200 mg/day) will be administered [15–17].
Control group (standard treatment)
In this group, NST (nicotine patches) at usual doses (21 mg/day first and second fortnight, 14 mg/day third fortnight and 7 mg/day fourth and last fortnight), will be offered.
Pharmacological treatments will be financed by the grant. It will be administered by a psychiatrist (JGC). Duration of treatment, in both groups, will be 8 weeks. All patients will have free use of nicotine gums or lozenges during the two months of the treatment.
Measurements
The study personnel that carried out the measurements (NS, AM, AC) will be unaware of which pharmacological treatment the patients is being administered ("blind"). The follow-up assessments will take place at baseline (clinical interview), D -1, D + 1, weeks 1, 2, 3, 4, 6, 8, 10 and 13, and months 4, 5, 6, 8, 10 and 12.
Variables and instruments of measurement (See Table 1)
Main outcome variables
In accordance with the aims of the study, the major outcome is tobacco cessation in patients with depression. The diagnosis of tobacco dependence will be made with the Spanish version of the MINI psychiatric interview substance dependence module adapted to tobacco [24]. This modification has been validated on a Spanish population with adequate psychometric properties [19]. Tobacco abstinence will be diagnosed by self-declared abstinence, self-administered Minnesota tobacco abstinence symptoms [25], expired air carbon monoxide [26], and cotinine in saliva. Tobacco abstinence, according to majoritarily-accepted criteria [27], has been defined using 2 concepts: 1. Occasional abstinence: In a follow-up visit, patients affirm that they have been abstinent, their levels of expired air carbon monoxide < 10 ppm, and cotinine levels in saliva < 5 ng/ml. Continuous abstinence: As of the visit at 30 days, patients affirm that they were abstinent the month before, expired air carbon monoxide levels < 10 ppm and cotinine levels in saliva < 5 ng/ml. Tobacco relapse will be diagnosed with the MINI psychiatric interview substance dependence module adapted to tobacco [24].
The diagnosis of depressive disorder will be made with the Spanish version of the MINI psychiatric interview, depression module [24], and the severity of the depression with the Spanish version of the Zung Self-Rating Depression Scale [22]. Recruitment will only include patients with depressive disorder and Zung scale scores < 60, which implies minimal to mild depression [22]. MINI psychiatric interview depression module [24], will be also used as criteria for depression relapse.
Secondary variables
- The following socio-demographic data will be collected: sex, age, marital status (single, married/relationship, separated/divorced, and widowed), education (no studies, primary, lower secondary, upper secondary, university), occupation and social class (I, II, IIIN, IIIM, IV and V of the British Registrar General's Scale) [28].
- Tobacco dependence as measured by the Spanish version of the Fagerström test for Nicotine Dependence [29].
- Anxiety trait and state as measured by the Spanish version of the State-Trait Anxiety Inventory (STAI) [30].
- Impulsivity as measured by the Spanish version of the Plutchik Impulsivity Scale [31].
- Visual analogue scale for efficacy self-perception (range 0–10).
- Pharmacological side-effect events from the medical record.
Statistical methods
Sample size
To calculate the sample size we consider the tobacco cessation rate at 1 year follow-up as the main outcome variable. On the basis of published research data [5, 6], we assume that this will be 35% in the control (NST) group, and we aim to detect a difference of 25% or more between any of the two groups (control and intervention). Published studies place placebo response at 10% [32]. Accepting an alpha risk of 0.05 and a beta risk of < 0.20 in a bilateral contrast, we would need 90 patients in each group [33].
Analysis strategy
The analysis will be per intent to treat. First we will compare the intervention group with the control group in order to verify that there are no significant differences between the two groups (socio-demographic characteristics, clinical baseline data, etc). We will use the mean (standard deviation) in the continuous variables and percentages in the categorical variables. For comparisons we will use the Student-t test for continuous variables and the Chi-squared test for categorical variables. Non-parametric tests may also be used.
The main variables of the result are the percentage of patients with tobacco cessation (patient's self-declared abstinence, expired air carbon monoxide levels, self-administered Minnesota tobacco abstinence symptoms, and cotinine levels in saliva), and tobacco dependence (Fagerström test for Nicotine Dependence scoring) at 1-year.
Process variables include severity of the depression (Zung Self-Rating Depression Scale), anxiety trait and state (STAI), impulsivity (Plutchik Impulsivity Scale), and efficacy self-perception (visual analogue scale).
We will use the general linear models of the SPSS 15 statistical package, to analyse the effect of the treatment on the categorical result variables (tobacco cessation rate). We will use the analyses of linear mixed models to analyse the effect of the continuous process variables (depression, anxiety, impulsivity and efficacy).
Ethical aspects
Informed consent will be obtained from the participants before they are aware of which group they are to be included in. Before they give their consent, the patients will be provided with a general overview of the aims and characteristics of the study and the multi-component intervention. They will also be informed that they will be participating voluntarily, and that they can choose to withdraw at any time with the guarantee that they will continue to receive the treatment considered most appropriate by their doctor.
The study follows Helsinki Convention norms and posterior modifications and the Declaration of Madrid of the World Psychiatric Association. The Study Protocol was approved by the Ethical Review Board of the regional health authority in February 2007 (ref: FIS PI06/1462).
Forecast execution dates
Initial recruitment of patients: March 2008
Finalisation of patient recruitment: December 2008
Finalisation of patient monitoring period: December 2009
Publication of results: June 2010