Schizophrenia is a debilitating condition impacting approximately 1% of the general population.2 Although there is a strong genetic predisposition to schizophrenia, there is also a risk in individuals with no family history of mental illness. As described in this Clinician Guide, a diagnosis of schizophrenia can be ominous, and there are few conditions that evoke similar degrees of concern, trepidation, and hopelessness. The impact does not fall solely on the individual with schizophrenia but also with their friends, colleagues, and family.

Schizophrenia is among the top causes of disability and functional burden worldwide, and the life expectancy of those with schizophrenia is approximately 15 years less compared to the general population.3 (More on prevalence rates of schizophrenia.) To maximize healthcare and mitigate this functional decline, the importance of having a strong multidisciplinary support system, including family, cannot be understated.

Our understanding of schizophrenia has progressed considerably since the advent of the antipsychotic chlorpromazine in 1951, which was considered a paradigm-shifting treatment. We now know that schizophrenia consists of both positive (eg, hallucinations and delusions) and negative (eg, alogia, anhedonia, blunted affect, avolition) symptoms as well as cognitive symptoms (eg, concentration, attention, memory). Symptoms of psychosis can also present with concurrent mood symptoms, such as depression or mania. (See the full DSM-5 definition of schizophrenia.)

Current pharmacologic treatment of schizophrenia involves antipsychotic medications, which function through antagonism or partial agonism at the dopamine D2 receptor. Second-generation antipsychotics, or atypical antipsychotics, also impact other receptors, such as antagonizing the serotonin 5-HT2a receptor. Antipsychotic medications are most effective at treating the positive symptoms rather than the negative or cognitive symptoms of schizophrenia, which often fail to completely remit.2 There is considerable heterogeneity between individual antipsychotic medications, and the treatment of schizophrenia can be personalized to maximize treatment efficacy and tolerability. Although effective, antipsychotic medications can precipitate adverse effects, including metabolic disturbances and movements disorders. Moreover, despite good efficacy, overall antipsychotic adherence remains poor.

The focus of this article therefore will be to address three common clinical challenges in managing and treating schizophrenia in order to best optimize treatment response. Described are medication adherence, metabolic side effects, and comorbid mood disorders.

First, see a sample dialogue on how to explain a schizophrenia diagnosis to patients, including potential medication side effects.

Scripted1.Explaining SchizophreniaF View full size image.


Medication Adherence in Schizophrenia

Regardless of the efficacy of a given pharmacotherapy, medications are ineffective in patients that do not take them. Less than 50% of patients with schizophrenia are adherent to pharmacologic treatment, and the number drops over time, with approximately 75% of schizophrenia patients becoming non-adherent within 2 years of hospital discharge.4,5 Unfortunately, results are similar in individuals following their first episode of psychosis.6


Pseudo-adherence occurs when providers falsely believe their patients are adherent to medication. Many times, providers are confident that their patients are adherent with treatment, only to later find that their patients were resistant to treatment, not treatment resistant. In a study of 99 patients (n=99) referred to a clinic for the management of treatment-resistant schizophrenia, approximately one-third were found to have either a subtherapeutic or undetectable serum level.7 Although there is not a clear relationship between antipsychotic plasma level and efficacy, and pharmacokinetics (eg, rapid metabolizers) could impact serum levels, an undetectable level is very telling and should result in a reevaluation of the current treatment. (See also, how ethnopsychopharmacology can help drive treatment response in people with schizophrenia.)

Risks of Nonadherence

Antipsychotic medication adherence is crucial because medication-free periods are more likely to result in psychotic decompensation and a stepwise decline in function. Patients with schizophrenia and their family will often ask if they need to remain on antipsychotic medication indefinitely. Patients may say that they will just take their medications if they feel (or are told) their symptoms are coming back. However, intermittent treatment (receiving treatment only after early signs of relapse) results in a higher rate of relapse when compared to continuous treatment.8 Moreover, antipsychotic medication nonadherence is associated with a 4-fold increase in relapse after a first episode of psychosis.9 After subsequent decompensations, response to antipsychotic treatment is often less robust, takes longer to occur, and requires a higher dosage of medication.10-12

Strategies to Improve Medication Adherence

Strategies to enhance medication adherence include but are not limited to:

  • psychotherapy and psychoeducation to enhance insight
  • family involvement
  • a strong therapeutic alliance
  • pill counts
  • encouraging reminders to take daily medications (eg, phone calls, visiting nurses/family, medication reminder apps on a phone or device)
  • observing medication administration to rule out ‘cheeking’ medicine

Antipsychotic plasma levels can also be obtained via drug monitoring to assess for low or non-existent serum levels, which may help to elucidate why there is a lack of therapeutic response. Another strategy to enhance treatment adherence is the use of a long-acting injectable (LAI) antipsychotic.

LAI antipsychotics are underutilized but can be a prudent option in a chronically nonadherent patient population. Ensuring that clinicians and staff are educated about the potential benefits of LAIs has been shown to increase their utilization.8 In a real-world effectiveness trial of nearly 30,000 patients with schizophrenia, for example, treatment with LAI antipsychotics had a 20% to 30% lower incidence of psychiatric rehospitalization than treatment with an equivalent oral formulation, and treatment adherence was considered major contributor.13 The dosing frequency of LAIs is becoming more flexible, with options ranging from every 2 to 12 weeks, with even less frequent options on the horizon. Although they are typically considered in patients having a history of nonadherence to treatment, there is also favorable evidence in patients with early-stage illness.14 Moreover, there are few differences in tolerability between LAI and oral antipsychotics.15

*See a sample dialogue on how to talk to patients and caregivers about the importance of medication adherence below.

Scripted2MedicationAdhrenceF View full size image.

Antipsychotic-Induced Metabolic Effects

The most common cause of death in individuals with schizophrenia is cardiovascular disease. The reasons for this are multifactorial. Individuals with schizophrenia have high rates of sedentary lifestyles, poor diet, obesity and nicotine dependence, and low rates of healthcare utilization.3 Moreover, antipsychotic medications can precipitate metabolic disturbances and weight gain. In fact, it has been suggested that these are not actually “side” effects, but rather “core” effects of antipsychotics.16

The rise of atypical antipsychotics or second-generation antipsychotics (SGAs) at the expense of typical antipsychotics first-generation antipsychotics (FGAs) has further exacerbated this issue because as a class, SGAs are more likely to induce metabolic syndrome.17 Despite this, numerous studies have identified the protective effects of antipsychotics for schizophrenia and a lower all-cause mortality rate for antipsychotic treated individuals compared to those treated without antipsychotic medications.18,19

Metabolic Dysregulation in Schizophrenia

There is considerable heterogeneity between individual antipsychotics and their degree of metabolic dysregulation. There also appears to be an inverse association between efficacy and metabolic tolerability, suggesting that the most efficacious antipsychotics (eg, clozapine) are associated with the greatest metabolic disturbance.17 Additionally, this is a patient population that is primed to experience metabolic syndrome. Studies have shown that at baseline, before the use of antipsychotic medication, individuals with schizophrenia have impaired lipid and glucose homeostasis.17,20

Strategies to Minimize Antipsychotic Metabolic Effects

Patient Education

ark Twain said, “It’s easier to stay out than get out.” Being mindful of this concept, it is easier to educate patients and families about antipsychotic-induced side effects and how to minimize them before they occur than it is to treat or reverse effects after they occur. In fact, antipsychotic-induced weight gain is more preventable than reversible.21 Almost all antipsychotics can cause metabolic disturbances, and in antipsychotic naïve patients, most weight gain occurs during the first 6 weeks of treatment.22 There are high rates of treatment response during the first episode of psychosis regardless of which antipsychotic medication is utilized.23 As a result, it is recommended to strongly consider a more metabolically neutral antipsychotic initially. (See also, weight gain and antidepressants in adolescents.)

Routine Monitoring

Prior to beginning antipsychotic treatment, baseline measurements should be taken, including weight, body mass index (BMI), hemoglobin A1c, fasting blood glucose, lipid profile, and blood pressure. Subsequently, routine monitoring of these measurements should continue, and significant changes should result in close collaboration with the patient’s primary care provider.24

Lifestyle Modifications

Before more complicated measures are taken, one of the most effective strategies to ameliorate metabolic disorders is lifestyle modifications. Recommendations can consist of diet, exercise, and encouraging a heightened awareness of any increase in appetite. If these strategies are unsuccessful, modifying the medication regimen should be considered.

Switching Antipsychotics

If necessary, a clinician may augment or switch to a more metabolically and weight-neutral medication. Before switching, the potential benefits need to be considered against the chances of symptom exacerbation (see a recent literature review on best practice). Switching before significant hyperlipidemia or weight gain occurs is more likely to be successful. Many times, switching is not an option. Either the patient has not responded to more metabolically neutral options, or they are responding so well to existing treatment that they are unwilling to risk symptom decompensation.

Metformin is a well-tolerated and affordable option that can attenuate and/or reverse antipsychotic-induced weight gain, and should be a strong consideration in patients with, or at risk for, insulin resistance.24 The optimal time to augment with metformin is before the weight gain has already occurred. As of June 1, 2021, there is a newly approved option for the treatment of schizophrenia, the oral combination olanzapine and samidorphan (Lybalvi). This combination pill has been shown to reduce olanzapine-induced weight gain. Samidorphan is not available as a single agent outside of this combination pill.21 If a high-risk metabolic offender, such as olanzapine, is being considered, consider prescribing samidorphan and olanzapine, if available, instead.

Schizophrenia and Comorbid Mood Disorders

Symptoms of schizophrenia do not occur independently in a vacuum – there are frequently psychiatric comorbidities. The occurrence of mood symptoms can cloud the diagnosis. A timeline of symptoms, therefore, needs to be established to determine the longitudinal course, as the preceding symptom will typically identify the illness (eg, bipolar 1 disorder with psychotic features, major depressive disorder [MDD] with psychotic features, schizoaffective disorder, or schizophrenia with associated mood symptoms).

Schizoaffective Disorder

Schizoaffective disorder, in particular, is a controversial diagnosis that requires that a major depressive or manic episode occur concurrently with schizophrenia symptoms for the majority of the total duration of active illness.25 The prognosis for schizoaffective disorder is likely midway between schizophrenia and bipolar disorder.26 Although only one antipsychotic is approved for the treatment of schizoaffective disorder, there is good evidence that others are also efficacious.27

Bipolar Mania

For symptoms of mania, consider the patient’s metabolic profile, response to prior antipsychotics, and goals of treatment, as most, if not all, antipsychotics are efficacious for the treatment of bipolar mania. After an insufficient treatment response, clinicians can justify switching to an alternative antipsychotic or augmenting with a mood stabilizer such as lithium, although strong data for augmentation with a mood stabilizer is lacking. (More on bipolar disorder treatment guidelines.)


Symptoms of depression that occur during the course of schizophrenia are common (7% to 75%) and require further investigation.28 Depressive symptoms could be attributable to negative symptoms of schizophrenia, antipsychotic-induced side effects, substance abuse, a comorbid medical condition, or a distinct major depressive episode. Depressive symptoms that occur during an acute episode of psychosis often improve as psychotic symptoms respond to treatment, and a wait-and-see approach can be initially justified.

If symptoms are considered secondary to an antipsychotic, consider switching to one with efficacy in treating unipolar or bipolar depression, as several are FDA approved. Additionally, ensure the patient is receiving an SGA rather than an FGA. When depressive symptoms meet the threshold for MDD and cause distress or impairment, consider augmenting with an antidepressant. There is no gold-standard antidepressant, which gives providers flexibility in individualizing treatment – consider whether the patient would benefit from an activating or sedating antidepressant, drug-drug interactions, prior history, etc.

Moreover, as with most types of mental illness, psychotherapy should not be overlooked, especially in newly diagnosed individuals. Most of us can appreciate the demoralization and despair that can accompany a new diagnosis of schizophrenia.

Dr. Faden Answers Key Questions on Treating Schizophrenia and Treatment Adherence in this video:

Clinical Takeaways on Treating Schizophrenia

Our understanding of schizophrenia continues to evolve, as do our strategies to treat this debilitating condition. Despite the complexity that can accompany a schizophrenia diagnosis, fostering hope and optimism in our patients and their families should begin on Day 1. Talking to individuals and their caregivers about the potential metabolic side effects of schizophrenia medications should be part of this communication. Fortunately, the strategies for ameliorating antipsychotic-induced metabolic dysregulation continue to evolve and grow. New combination tablets are being developed, and there is an increased emphasis on selecting medications with favorable metabolic profiles and swiftly addressing metabolic derailments. Baseline measurements should be taken and routinely followed.

However, for a medication to be effective, it needs to be taken. A lack of insight into schizophrenia symptoms is so common that treatment nonadherence should come as no surprise to clinicians. A strong therapeutic alliance, a family support system, and early psychoeducation are some strategies to optimize adherence.

Lastly, examine whether all symptoms are being treated. Should depressive symptoms surface, for instance, the clinician should act as a detective to determine the source and treat accordingly.

While the overall prognosis of schizophrenia remains guarded, a savvy clinician can still work to provide the best personalized care possible.

Back to the full Clinician Guide on Treating Schizophrenia.

Last Updated: Oct 4, 2021