According to the WHO, 280 million people are diagnosed with depression, the prevalence of which is almost twice as high in women as in men, with the incidence among young people increasing in recent years. Another public health problem in Spain is tobacco consumption, with one in four adults being tobacco users. The presence of an addiction and another mental illness in the same patient is called dual disorder, and it is very common for depression to be associated with smoking. This is due to a shared biopsychosocial vulnerability between the two disorders. Although there are currently pharmacological treatments that address both disorders, their efficacy is limited; in this sense, transcranial magnetic stimulation (TMS) offers a way to treat these dual disorders. TMS is a technique in which a magnetic field is applied to the cortex through a coil, generating an electric current that can induce changes in the different neurotransmitter systems, stimulating or inhibiting them. A randomised, double-blind, placebo-controlled clinical trial is proposed to evaluate the efficacy of TMS in the treatment of a sample of 36 patients with resistant major depression and nicotine dependence. Both depression and smoking will be assessed at baseline, at various times during treatment and at the end of the study using psychometric tests, neurophysiological and biochemical assessments. It is expected that the experimental group will show improvements in depression, nicotine dependence and certain cognitive functions. TMS treatment of dual disorders (resistant depression + smoking) could represent a health and social advance, especially for women.

Currently, resistant major depression and substance abuse disorder are two highly prevalent mental health pathologies. In the case of depression, the WHO estimates that 3.8% of the world's population suffers from this disorder, which is the result of a complex interaction between social, biological and psychological factors. Multiple sociodemographic factors are related, such as low socioeconomic status, which results in a poorer physical condition that predisposes to depression. In addition, there is also a strong association with different mental illnesses, when associated with an addiction it is called Dual Disorder, with tobacco or alcohol consumption being more frequent. Other factors to highlight are a history of trauma in childhood, being in a situation of divorce/separation, but there is especially a strong association with the female gender. Although the prevalence in the female gender is much higher, no difference is observed with respect to men in terms of the course of the disease and the risk of relapse. The higher incidence of depression in women can be attributed to different factors: biological reasons (hormones and genetic load), psychological reasons (neuroticism, lack of positive affect, rumination or personal dissatisfaction), without forgetting environmental factors: such as sexual abuse or violence in childhood, as well as social inequalities between men and women. This clear difference between women and men justifies and demands the incorporation of a gender perspective in the research, management and treatment of patients diagnosed with major depression. The importance of major depression also lies in the fact that it is the fourth cause of death in the age group between 15 and 29 years and is a common cause of temporary disability due to common contingencies in people of working age, with durations of around 6 months, much longer than the duration estimated by the National Institute of Social Security of 30-60 days. This is reflected in the economic costs, which are estimated to result in an annual public expenditure of up to 10,763 million euros. It is a complex disease that is expected to see its incidence increase in the coming years, which is why it requires a scientific effort for its diagnosis and treatment, especially in resistant cases, because they evolve into a chronic mental illness with higher personal, social and health costs. Nicotine use disorder is also a public health problem, with 50,000 deaths currently attributed to it. The prevalence of 1 in 4 individuals makes it the most common mental illness. Although there has been a decline in consumption among men in recent years, this is not reflected in the same way among women. There are many factors that determine vulnerability to nicotine use disorder, both genetic and psychosocial, highlighting that the early onset of consumption predisposes to a higher risk of addiction, given the brain immaturity in certain brain circuits. Due to biopsychosocial factors common to other mental disorders, it is common for patients with tobacco addiction to present dual disorder, especially depressive disorders. An example is the CHRNA5 gene, encoding the alpha 5 subunit of the acetylcholine receptor, related to nicotine dependence, but also to an increased risk of suffering from mental disorders and, therefore, dual disorders.

It is therefore not an isolated or coincidental fact that both diagnosis coexist in the same individual, an affective disorder such as major depression with addiction to a substance, such as tobacco, which is called dual disorder.

In this group of patients, there is a fact worth mentioning, and that is that both diseases present an increased risk of suicidal ideation. In the case of depression, this relationship has been clearly studied, but an increased risk has also been observed in patients who are smokers or who have been smokers, which is why it is an item that has been included in different clinical scales that assess this ideation. This symptomatology requires special attention for diagnosis and treatment due to its potential lethality.

The need for new lines of treatment arises because in depression, up to 30% of patients are resistant to pharmacological therapies. Although electroconvulsive therapy is currently considered the treatment of choice for resistant depression, it has important limitations, for example due to the need to anesthetize the patient, as well as the frequent side effects that it has on cognitive functions, specifically memory loss, which make it a technique with little social acceptance. Something similar occurs with regard to nicotine use disorder. With the use of drugs such as varenicline (recently withdrawn from the market) or cytisine, the drug of choice currently for the treatment of this disorder, it is observed that only 32% of patients remain abstinent two weeks after having finished the treatment, along with the side effects that make adherence to the treatment difficult.

As a result of the therapeutic limitations described above, neuromodulation techniques, such as the one proposed in the present study: transcranial magnetic stimulation, have gained prominence in recent years.

The technique is based on Faraday's Law of electromagnetic induction. The use of a stimulation coil placed on the patient's head generates a pulse of electric current that produces a magnetic field that passes through the scalp and the cranial vault without attenuating (it only decays with the square of the distance). This magnetic pulse gives rise to a selective depolarization of neurons in the cerebral cortex, located 1.5-2 cm below the cranial vault, in such a way that it modulates their activity either by inhibiting or stimulating their effects. This entire process will depend on the shape, size, type and orientation of the coil, the strength (intensity) of the magnetic field and the frequency and duration of the transferred magnetic pulses, resulting in stimulation or inhibition of the selected areas. In addition, these changes are not restricted only to the stimulated/inhibited area, but also influence other cortical and subcortical regions through brain circuits and connections.

The FDA approved the application of the technique as a treatment for major depression in 2008. Different protocols have been approved for the treatment of this diagnosis, establishing as the main target the left dorsolateral prefrontal cortex, an area of easy accessibility for the application of the technique and which, together with others such as the cingulate region, temporal and parietal cortex regions, thalamus, hypothalamus and striatum, show hypometabolism in functional imaging tests, these alterations being, along with others, responsible for the clinical manifestations of depression.

For the treatment of tobacco addiction, the FDA approved the application of the technique in 2020, with the left dorsolateral prefrontal cortex and the insular cortex also being cortical targets. The stimulation of these two areas aims to generate changes in the mesolimbic and mesostriatal dopaminergic circuits, two regions involved in the neuropathology of addiction.

Thus, transcranial magnetic stimulation is an approved technique for the treatment of major depression and nicotine use disorder, but independently for each mental disorder. Dual disorder is also common, that is, the presence in the same patient of an addiction (nicotine) and another mental illness (major depression), and this clinical trial is proposed to evaluate the efficacy and tolerability of transcranial magnetic stimulation in patients resistant to conventional treatment, and where women are a more vulnerable group. Regarding suicidal ideation, TMS has also demonstrated its efficacy in reducing the risk in depressed patients, but not in the case of an individual with both disorders. Investigators propose this trial as an opportunity to evaluate it after applying a protocol that treats both simultaneously.

Inclusion Criteria:

• Patients over 18 years of age being monitored in the mental health area of the province of Castellón, with a dual disorder: major depression and substance abuse disorder
• Patients who are refractory to two or more lines of pharmacological treatments, ensuring correct completion beforehand
• Acceptance of informed consent

Exclusion Criteria:

• Psychotic symptoms or catatonia
• Other addictions, or psychiatric or personality disorders
• Language barrier
• Mental retardation that will interfere with the ability to understand and subsequent acceptance or rejection of informed consent
• Patients diagnosed with epilepsy
• Patients diagnosed with a space-occupying lesion in the brain
• Tinnitus
• Confirmed pregnancy; if suspected, a test will be requested
• Metal piece in the body or implanted medical device, except for dental material

The data will not publicly available due to privacy or ethical restrictions.