Depression is one of the most common mental disorders. Epidemiological studies indicate a growing risk of depression as a complication of chronic or severe somatic diseases. Depression itself has also a significant influence on the course and efficacy of therapy of many somatic diseases, thus the relationship between depression and physical illness is bidirectional. There is convincing evidence of comorbidity of depression and diseases such as diabetes, stroke, cardiovascular diseases, cancer, dementia, chronic pain or infectious diseases. Given the prevalence of these diseases and a high population risk of depression, primary care physicians should be prepared to carry out diagnosis and implement proper treatment. Due to the nature of general practitioners’ work, diagnosis of depressive disorders should be limited to the essential minimum. Both current diagnostic criteria as well as simple lists of symptoms may occur helpful. Pharmacotherapy is an effective and widely available treatment of depressive disorders. It is emphasised to individualise the selection of the right antidepressant in a group of patients with somatic burden. When choosing the drug, it is vital to take into account not only depressive symptoms. Potential side effects of antidepressants and their interaction with other drugs are equally important. In the following study, in addition to the characteristics of co-occurrence of depression and somatic diseases as well as guidelines for the diagnosis of depressive disorders, the choice of drugs with proven antidepressant efficacy is presented. Their safety profiles enable their use in outpatient settings.