Assessing and Measuring Nonresponse in Schizophrenia

John M. Kane, MD

Department of Neurology and the Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine of Yeshiva University, New York; Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks; and Behavioral Health Services, North Shore-Long Island Jewish Health System, Hyde Park, New York

Symptom resolution, relapse prevention, and recovery of function are the goals of schizophrenia treatment. Pharmacotherapy is the main treatment for schizophrenia, and atypical antipsychotics are recommended as first-line treatment options,1 mainly due to their lower tendency to cause EPS than typical antipsychotics.2 While the atypicals have been thought to be more similar to each other than to the typicals, slight differences in efficacy and side effects exist within the class3; therefore, the choice of medication for a particular patient should be made with regard to that patient’s needs. Considerations in choosing among antipsychotics include the patient’s history of psychosis and treatment response, comorbid medical and psychiatric conditions, and vulnerability to specific adverse effects, as well as the patient’s insight into the nature of schizophrenia and personal preference regarding treatment.4

Schizophrenia is a chronic illness that requires long-term treatment. Developing a long-term treatment plan requires assessing patients’ acute-care treatment progress and making adjustments to their medication regimen as necessary. Clinical decisions include deciding whether the patient’s response to treatment is adequate, deciding when or if medication should be changed due to inadequate response or intolerable adverse effects, and determining when the locus of care can be changed from a hospital setting to an outpatient setting.

Value of Measurement-Based Assessments

Although various objective means of determining response are available, clinicians often rely on clinical impressions and informal interviews to make an overall judgment as to whether a patient has improved. However, measurement-based tools are a valuable part of both diagnosis and the ongoing treatment process. During diagnosis, tools help to establish a baseline measure of the severity of a patient’s psychopathology, and in the treatment process, they help to demonstrate change from those baseline measures, which can be used to assess response to treatment. Measurement-based tools can provide treatment targets and goals that are helpful in communicating with patients and their families about the treatment process. Rating scales quantitatively evaluate symptomatic improvement and adverse effects experienced by patients. Objective measurements should be included in the patient’s medical record to accurately document the patient’s care and reflect the course of treatment.


Tools for assessing schizophrenia symptomatology include the PANSS , the BPRS, and the CGI scales. The AIMS can be used to measure tardive dyskinesia. Adverse effects can also be monitored using the ASC. To assess metabolic side effects, clinicians should record baseline measurements of the patient’s weight, height, waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile, and then perform follow-up monitoring at recommended intervals5; a metabolic syndrome monitoring log can be used.

Assessing Treatment Response

AV 1. Corresponding Clinical Global Impressions (CGI) and Positive and Negative Syndrome Scale (PANSS) Scores (00:36)

Data from Leucht et al6
CGI-Severity is rated on a 7-point scale: 1 = normal (not at all ill), 2 = borderline mentally ill, 3 = mildly ill, 4 = moderately ill, 5 = markedly ill, 6 = severely ill, and 7 = among the most extremely ill patients
CGI-Improvement is rated on a 7-point scale: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse

Response to treatment can be defined as a certain numeric reduction or percentage of improvement in symptom scores. Clinical trials often use a 20% reduction of symptoms from baseline on the PANSS to indicate response; in clinical practice, however, that percentage translates to "minimally improved" on the CGI-I scale, and a reduction closer to 50% may be necessary for the patient to be considered "much improved" (AV 1).6 If the patient’s symptom improvement is adequate, the goal of treatment becomes remission.

If the patient has had an adequate treatment duration but a suboptimal response, clinicians should consider several factors before switching medications. First, the diagnosis and the patient’s adherence to the medication should be confirmed. Blood drug levels can then indicate if the medication is in the therapeutic range. Clinicians may choose to increase the dose to try to increase response, or lower the dose if side effects are affecting adherence and response. For continued suboptimal response, clinicians might consider augmenting treatment with an agent of either the same or a different class before switching medications.

A question that arises when measuring response is, "How long do I wait before considering the antipsychotic as lacking in efficacy for this patient?" In an expert survey,2 opinions ranged from 2.5 to 5.5 weeks, indicating a lack of consensus regarding the adequate duration of a treatment trial. The time range may also be unrealistic in practice, as inpatient hospitalizations for patients in an acute episode are generally no more than 2 weeks.

AV 2. Prediction of Treatment Response at 3 Months by Early Treatment Status (00:34)

Data from Kinon et al7

 One way to counter time constraints may be to use early response/nonresponse as a predictor of subsequent response/nonresponse. In a post hoc pooled analysis,7 patients with minimal early response (≥ 20% reduction in PANSS scores within the first 2 weeks) continued to show greater response throughout the treatment trial than did early nonresponders. Nonresponse during the first 2 weeks was a strong predictor that a patient would not respond subsequently (AV 2). Additionally, a prospective study8 found that early nonresponders who were switched to another medication at week 2 had better outcomes at 12 weeks than those who were maintained on their initial antipsychotic.


Using measurement-based tools to assess patients helps in the diagnosis of schizophrenia and establishes a baseline level of symptom severity. When choosing among antipsychotics, the patient’s individual needs should drive the decision-making process. Clinicians should assess acute-care medication response by comparing current symptom measurements against baseline measurements and then use this information to develop a long-term treatment plan. Full documentation of medication trials and measurements of response is essential for long-term treatment planning. Clinicians with time constraints during acute-care medication trials can use as a guideline evidence showing that patients who do not experience minimal response to an adequately dosed medication within 2 weeks are unlikely to respond subsequently. For patients with suboptimal response to treatment, clinicians can consider augmenting their medication or switching to a new medication.

For Clinical Use

Use rating scales to establish a baseline measurement of symptom severity

Use measurement-based tools to evaluate symptom improvement and tolerability of adverse effects

Assess patients for early response or nonresponse to inform treatment decisions


AIMS = Abnormal Involuntary Movement Scale, ASC = Antipsychotic Side-Effect Checklist, BPRS = Brief Psychiatric Rating Scale, CGI-I = Clinical Global Impressions-Improvement scale, CGI-S = Clinical Global Impressions-Severity scale, EPS = extrapyramidal symptoms, PANSS = Positive and Negative Syndrome Scale


1. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, 2nd ed. Published April 2004. Accessed November 8, 2011.

2. Kane JM, Leucht S, Carpenter D, et al. The Expert Consensus Guideline Series: optimizing pharmacologic treatment of psychotic disorders. J Clin Psychiatry. 2003;64(suppl 12):1–100. Full Text

3. Leucht S, Komossa K, Rummel-Kluge C, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry. 2009;166(2):152–163. PubMed

4. Kane JM, Correll CU. Pharmacologic treatment of schizophrenia. Dialogues Clin Neurosci. 2010;12(3):345–357. PubMed

5. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, et al. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267–272. Abstract

6. Leucht S, Kane JM, Kissling W, et al. What does the PANSS mean? Schizophr Res. 2005;79(2–3):231–238. PubMed

7. Kinon BJ, Chen L, Ascher-Svanum H, et al. Predicting response to atypical antipsychotics based on early response in the treatment of schizophrenia. Schizophr Res. 2008;102(1–3):230–240. PubMed

8. Kinon BJ, Chen L, Ascher-Svanum H, et al. Early response to antipsychotic drug therapy as a clinical marker of subsequent response in the treatment of schizophrenia. Neuropsychopharmacology. 2010;35(2):581–590. PubMed