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APA Releases New Practice Guideline for the Treatment of Patients with Schizophrenia

18 Mar 2021 6:01 PM | Anonymous

By: Garrett Shobe; PharmD Candidate 2021

Mentor: Leigh Anne Nelson, PharmD, BCPP; Associate Professor of Pharmacy/Psychiatry, UMKC School of Pharmacy

Schizophrenia is a chronic disabling thought disorder resulting in severe detrimental effects to a person’s health, social, and occupational status. Individuals with schizophrenia can present with hallmark symptoms of psychosis (delusions, hallucinations, disorganized speech), negative symptoms (avolition, anhedonia), catatonic behavior, and cognitive dysfunction. People with schizophrenia have significantly higher rates of mortality as compared to the general population, especially in the presence of other psychiatric or substance use disorders and unfortunately, approximately 10% die of suicide. The American Psychiatric Association (APA) developed a new practice guideline in 2020 focused on the treatment of schizophrenia. The APA recommendations for use of first-generation antipsychotics (FGA), second-generation antipsychotics (SGA), treatment resistant schizophrenia, long-acting injectable antipsychotics (LAIA), and first-episode psychosis will be reviewed.

The APA practice guidelines recommend patients with schizophrenia be treated with an antipsychotic medication. Contrary to other treatment guidelines, it is difficult to take an algorithmic approach when selecting an antipsychotic medication for schizophrenia. Selection of an antipsychotic medication should be based upon patient specific characteristics and antipsychotic adverse effects. Efficacy of antipsychotics are similar with the exception of clozapine. Clozapine is the only antipsychotic medication to demonstrate superiority over other antipsychotics in clinical trials but is recommended for use only after failure of two antipsychotic trials. Additionally, its use is restricted to patients through the REMS program and mandates monitoring of absolute neutrophil counts due to the boxed warning for potential risk of developing life-threatening agranulocytosis. Metabolic disorders and cardiovascular disease are common in patients with schizophrenia and can be worsened by the use of antipsychotic medications. APA recommends working along-side the patient, and/or caregiver to assess for past treatment failures, tolerability issues, and future treatment preferences. As a healthcare practitioner, identifying target symptoms such as anxiety, insomnia, hallucinations, and delusions can help guide decision making when differentiating between antipsychotic medications.

FGA such as chlorpromazine, fluphenazine, haloperidol, loxapine, thiothixene, and others work by antagonizing dopamine (D2) receptors and are associated with a higher risk of extrapyramidal symptoms (EPS) (i.e. pseudoparkinsonism, dystonia, and akathisia and most concerning and stigmatizing, tardive dyskinesia (TD). Due to the higher risk for EPS and TD, FGA are usually reserved for patients who are unable to tolerate, or who have failed trials with a SGA. However, APA suggests that if a patient is prescribed an antipsychotic medication (FGA or SGA) and their symptoms have improved, they should continue taking the same medication and have movement disorder assessments for EPS and TD be conducted on a scheduled basis. FGA fall into the treatment guideline as primarily second line therapy to treat positive symptoms such as delusions and hallucinations.

SGA are used first line in schizophrenia. The undesirable side effect profile of FGA led to the development of SGA. Most SGA (clozapine, olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, lurasidone, asenapine) work by blocking both dopamine (D2) and serotonin (5-HT2A) receptors. These agents are associated with significant metabolic disturbances (weight gain, hyperlipidemia, hyperglycemia). Olanzapine and clozapine exhibit the highest risk for metabolic side effects. Risperidone, paliperidone and quetiapine are considered to possess moderate risk, while ziprasidone and aripiprazole are lowest risk. Newer SGA also fall into the lower risk category for metabolic side effects. Aripiprazole, brexpiprazole, and cariprazine have a unique mechanism of action acting as dopamine (D2) partial agonists and also antagonize serotonin (5-HT2A) receptors. Overall, SGA are associated with a lower risk of EPS and TD as compared with FGA. When selecting a SGA, it important to understand the activity of each drug at the histamine (H1), muscarinic (M1) and alpha1/2 receptors, and review labeling for common side effects that can affect adherence.

Treatment resistant schizophrenia (TRS) is defined as having persistent symptoms of psychosis despite receiving adequate treatment with antipsychotic medications. Patients classified with TRS will have shown no or partial response to antipsychotic treatment (<20% decrease in symptoms) over the course of six weeks to two antipsychotic trials. APA recommends patients with TRS to be treated with clozapine. In addition to TRS, patients with schizophrenia who are at risk for suicide and/or display aggressive behavior despite receiving treatment with other antipsychotics should be evaluated for treatment with clozapine. To initiate clozapine, baseline ANC must be greater than 1500/mm3. After initiation, ANC should be monitored weekly for 6 months, then every 2 weeks for 6 months, then monthly thereafter. Clozapine therapy should be stopped if a patients ANC drops below 1000/mm3, develop suspected myocarditis, or experiences a cardiomyopathy.

APA practice guidelines recommend utilizing LAIA for patients who prefer LAI formulation, or have a history of poor or uncertain medication adherence. LAIA can improve medication adherence, are predicted to decrease hospitalizations, and improve outcomes for patients with schizophrenia. FGA medications available in a LAI formulation include fluphenazine decanoate and haloperidol decanoate. SGA medications available in LAI formulations include aripiprazole (Abilify Maintena, Aristada Initio, Aristada), olanzapine (Relprevv), paliperidone (Invega Sustenna, Invega Trinza), and risperidone (Risperdal Consta, Perseris). It is important to understand that these medications have unique formulations, loading capabilities, titration patterns, pharmacokinetics, and adverse effects. For example, FGA LAI have sesame oil-based vehicles while SGA LAI are water-based. Many of the LAIA require oral antipsychotic overlap when initiating therapy, so it is important to individualize treatment plans to your patient, and their circumstances.

For individuals experiencing their first episode of psychosis, APA recommends being treated in a coordinated specialty care (CSC) program. CSC programs were developed to provide evidence-based interventions, including antipsychotic medication, and to help patients recover after an initial schizophrenia episode. CSC programs provide individual resiliency training, employment and education assistance which allows them to feel a sense of accomplishment while developing autonomy. CSC programs utilize a collaborative, team-based approach, incorporating family involvement and education into a patient’s treatment plan. In combination with antipsychotic medication and cognitive-behavioral therapy for psychosis, CSC programs have been associated with a reduction in mortality, improved quality of life, and a greater likelihood of being able to return to work or school after receiving up to two years of treatment. Once again, selection of an antipsychotic is based on patient characteristics and antipsychotic medication adverse effects with SGA being more commonly tolerated and prescribed than FGA.

To improve the quality of care and treatment outcomes for patients with schizophrenia, APA developed this updated practice guideline for the treatment of schizophrenia as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). This guideline provided new recommendations for TRS, use of LAIA and first episode psychosis.


  • American Psychiatric Association: Practice Guideline for the Treatment of Patients with Schizophrenia, 3rd Edition. Arlington, VA, American Psychiatric Publishing, 2020. Accessed on 2/17/2021. https://doi.org/10.1176/appi.books.9780890424841

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