Patients with schizophrenia frequently have psychiatric comorbidities, including anxiety, depression, and substance use disorders. In addition, nonpsychiatric conditions such as metabolic syndrome, type 2 diabetes, hypertension, and hyperlipidemia are common. Interestingly, many of these comorbidities emerge prior to, and independent of, the onset of the psychosis symptoms. It is important to note that antipsychotic treatment, either alone or in combination with other medications, may impact a patient’s comorbid conditions or may increase the risk of developing comorbid conditions. Optimal care can be accomplished through a shared decision-making process, with a full understanding of the patient’s complete medical profile, to arrive at a suitable treatment plan together with the patient.

Managing comorbidities in patients with schizophrenia may involve a combination of nonpharmacologic approaches (eg, exercise and lifestyle modification) and pharmacotherapy. Many individuals with schizophrenia find it difficult to follow their clinician’s guidance, possibly because they do not have access to health care resources or adequate social support. For some, it is a constant struggle. Therefore, tracking all health problems, including both psychiatric and nonpsychiatric comorbidities, is essential in managing the overall health of patients with schizophrenia.

Psychiatric comorbidities are common in patients with schizophrenia, even after positive symptoms have been controlled. Approximately 56% have some degree of comorbid anxiety or depression; depression, in particular, is a common and persistent problem. A European study followed 107 first-episode patients for 12 years after initial diagnosis and found that a significant proportion (40%) had persistent depressive symptoms. For such patients, antipsychotic agents that improve the positive symptoms of schizophrenia and have inherent antidepressant properties might be an appropriate option, as is the use of antidepressant medication in those with no history of mania (eg, schizophrenia or schizoaffective disorder, depressed type).

Two antipsychotics, cariprazine and lurasidone, have been approved by the US Food and Drug Administration (FDA) as monotherapy for bipolar depression. An older agent, quetiapine, also has antidepressant properties but is often avoided because it can cause excessive sedation and weight gain. A newer antipsychotic, lumateperone, is awaiting an FDA decision in December 2021 for bipolar depression based on 2 positive studies. Those agents with dual indications for schizophrenia and bipolar depression may possibly be beneficial in patients with schizophrenia and comorbid depression, although some patients may still require antidepressant therapy.

In addition to psychiatric comorbidities, clinicians should remain mindful of medical comorbidities. For example, hepatic disease, which is a substantial public health burden, can greatly alter the metabolism of antipsychotic medications. For this reason, the FDA includes dosing information related to Child-Pugh stage in the package inserts of antipsychotic drugs so that one can determine a patient’s ability to metabolize a drug hepatically. If a patient is designated as Child-Pugh A, an antipsychotic agent can be given without dose adjustment. Child-Pugh B (ie, moderate hepatic disease) may call for a dose adjustment. Child-Pugh C (ie, severe hepatic impairment) may preclude the use of the drug. The Child-Pugh score is calculated using 3 laboratory parameters (ie, serum albumin, total bilirubin, and international normalized ratio) and 2 clinical criteria (ie, ascites and hepatic encephalopathy). The extent to which dose modification is required for any antipsychotic agent in patients designated as Child-Pugh B or C can be found in the labeling information for newer antipsychotics that were approved in the last 2 decades.

Some side effects can be less of a concern when the antipsychotic agent is administered acutely in the hospital, and the priority is simply to provide a medication that will reduce a patient’s acutely exacerbated positive symptoms, ensure the safety of the patient, and allow for hospital discharge. However, a medication that a patient will be receiving on a longer-term, post-discharge basis does require a comprehensive consideration of tolerability and how it can affect overall health, functioning, and adherence.

Regarding comorbidities and preexisting conditions, a study was conducted that examined health plan data and looked at the choice of antipsychotic therapy in view of the patient’s history (eg, cardiovascular disease or endocrine abnormalities). The investigators found that many patients were taking antipsychotics that can potentially worsen their comorbid conditions. Thankfully, the availability of multiple second-generation agents allows clinicians to have more options to choose from, and this helps reduce the adverse impacts of therapy on preexisting comorbidities. In addition, unlike first-generation antipsychotics, some of the second-generation agents appear to have a fairly broad spectrum of action and may therefore improve some psychiatric comorbidities (eg, regarding depression, as noted above). Regardless, clinicians can consider adding a second psychotropic agent (eg, an antidepressant) to an antipsychotic regimen if it would be beneficial to the patient.

Finally, another aspect of individualization is the option of offering long-acting injectable antipsychotics. Although we have a limited array of choices in terms of the molecule, the formulation itself can benefit many patients and may be a patient’s preferred choice.