BACKGROUND: Schizophrenia is a highly heterogeneous disease, and a high percentage of patients are at high risk of developing somatic comorbidities, which must be taken into account in disease management and treatment selection. MAIN BODY: Antipsychotics are often associated with side effects that worsen the somatic comorbidities. Among the different options, cariprazine is generally safe and usually well tolerated in both acute and long-term treatment and is often a good choice when balancing clinical benefits and side effects. Given the lack of consensus on the priority of symptoms to treat and the reasons for switching therapy based on the balance between side effects and symptom resolution, twelve psychiatrists met for an expert meeting to discuss the most common and worrisome antipsychotic side effects leading to switching, the most important somatic comorbidities, and the best way to address specific symptoms in both the acute and maintenance phases of treatment in schizophrenia. Special attention was given to metabolic comorbidities, sexual dysfunction, and cardiovascular disease. This paper aims to examine the relationship between schizophrenia and specific somatic comorbidities, to discuss how the balance between efficacy and tolerability influences treatment choice in the acute and maintenance treatment of schizophrenia, and how these two variables may have different priorities at different stages of treatment. CONCLUSION: The choice of treatment is based primarily on efficacy and tolerability. Cariprazine is beneficial in patients with positive and negative symptoms, and it has a side-effect profile with low rates of metabolic side effects, sedation, and sexual dysfunction.