Until recently, the most problematic group of side effects associated with antipsychotics has been extrapyramidal symptoms (EPS). However, the introduction of newer atypical antipsychotics has made it possible for patients to experience the benefits of antipsychotics while experiencing far fewer EPS. This development has resulted in a considerable reduction in the side-effect burden of antipsychotic treatment, but has also meant that clinicians now need to shift clinical attention to other, non-EPS side effects.
Most research on the assessment of antipsychotic side effects has focused on EPS, and a number of scales have been developed for assessing EPS, including the Abnormal Involuntary Movement Scale (AIMS) 1 for tardive dyskinesia (TD), the Barnes Akathisia Rating Scale 2 for akathisia, and the Simpson-Angus Extrapyramidal Side Effects Scale 3 for parkinsonian symptoms such as tremor. These scales, and others like them, have played a key role in increasing our understanding of the epidemiology of EPS in patients receiving antipsychotics and have facilitated comparisons of the relative EPS profiles of different antipsychotic medications. For example, the use of the AIMS was crucial in setting universal standards for the assessment of TD. In addition, when standardized EPS scales were compared to routine clinical assessments, substantial problems with the recognition of EPS in clinical practice were documented. 4,5 These kinds of studies ultimately led to the inclusion of diagnostic text and criteria for medication-induced EPS in Appendix B of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV). 6
Despite their usefulness, these important side-effect scales have some drawbacks:
* Current scales emphasize objective severity at the expense of subjective distress. For the most part, EPS scales measure the objective severity Cited Here... of side effects rather than the subjective distress they cause. However, in practice, subjective distress is often at least as important as severity. For example, the subjective report is a much more relevant predictor of noncompliance than objective measures. 7-9 Therefore, it is clinically important to have scales that assess the distress caused by side effects as well as their severity.
* Few scales assess for non-EPS side effects. As atypical antipsychotics replace older antipsychotics, most patients will experience fewer EPS. As a result of this reduced EPS burden, patients will become more concerned about other, non-EPS, side effects. The most common non-EPS side effects that patients report are weight gain, sexual difficulties, sedation, and amenorrhea. 10 We do not yet have any side effect scales to evaluate these problems that are as widely used and well validated as the EPS scales discussed above.
* There is a lack of scales that nonphysicians can use to screen for common side effects of antipsychotic medications. Many of the currently available side-effect scales must be administered by a physician or require special training. This is especially true for the EPS scales, which require the ability to test for specific neurologic signs such as muscle rigidity or choreiform movements. Unfortunately, in some settings, physician contact may be infrequent or very brief, and most actual patient contact is with non-physician mental health personnel. The net result is that physician-based side effect examinations may not be done routinely, and the currently available EPS measures may be beyond the skills of the staff working with the patient on a day-to-day basis. Fortunately, an assessment of physical signs is not needed to measure subjective distress, since, by definition, patient report is the most relevant factor in assessing distress and is much more amenable to screening measures administered by non-medical personnel.
In this article, we first discuss the kinds of subjective distress that can arise from the side effects of antipsychotics. We then present two new scales that have recently been developed to foster improved communication between patients and clinicians concerning the side effects of antipsychotics and the subjective distress associated with them. In the last part of the article, we discuss how to use these scales in day-to-day clinical practice. The actual scales and a training guide for users are provided on pages 64-72.
WHICH SIDE EFFECTS ARE MOST DISTRESSING TO OUR PATIENTS?
It is very important for clinicians to understand which side effects are most distressing to our patients and know how to assess for them. This is important no matter what type of antipsychotic medication is being used. Key questions in this area include:
* Which side effects are most bothersome?
* Do objective measures of side effects correlate with subjective distress?
* How do the newer atypical antipsychotics differ from the older conventional agents in terms of the most common causes of distress?
* How can we accurately assess for the common distressing side effects of both the newer and older antipsychotic medications?
To begin to answer these questions, we undertook a series of studies to evaluate:
1. the relationship between spontaneous reporting of side effects and side effects as elicited by objective and subjective rating scales to determine if focused interviews are more sensitive in eliciting distress than open-ended queries
2. the relationship between distress from side effects and phase of illness
3. the profile of side effect related distress reported with older compared to newer antipsychotic medications
1. Measuring Subjective Distress
The subjective distress associated with side effects is influenced by many factors unrelated to the direct pharmacologic effects of a medication. This creates a problem because subjective responses are messy. There are no quantitative measures of subjective distress, and consequently our clinical training tends to make us more comfortable evaluating the severity of side effects. Both the positive and negative symptoms of schizophrenia can also affect how the distress caused by side effects is reported. For example, it is well known that paranoid symptoms can make a person more vigilant and less likely to report any side effect. On the other hand, relief from terrifying psychotic symptoms may attenuate any distress from side effects.
Other kinds of deficit symptoms also make it much harder to elicit reports of distress. For example, some patients with schizophrenia seem to be insensitive to pain, 11 and many patients appear to be unaware of or indifferent to physical pain and distress. When describing schizophrenia at the turn of the century, Bleuler wrote, These patients don't care if they lie on a snowbank or go into a red hot oven… (p. 41). 12 Such indifference often causes our patients to underreport distress from side effects that would otherwise be troublesome. 13 The practical implication of this literature is that clinicians need to be pro-active in order to elicit any subjective distress that might otherwise go unreported because of the patient's negative symptoms.
One of the authors (PJW) conducted a study of subjective side-effect burden in the early 1990s before the new atypical antipsychotics were introduced. We studied the subjective burden of the side effects of conventional antipsychotics in a cohort of 92 patients with schizophrenia treated with conventional antipsychotics. We recruited acutely psychotic, relapsing inpatients with a diagnosis of schizophrenia or a related disorder and followed these patients during their hospitalization and after discharge. Details of the overall study design are reported elsewhere. 9,14 One of the major goals of this study was to better understand the relationship between objective and subjective side effects, and how these variables affect medication compliance. Objective EPS were measured with a physical examination for EPS using the Extrapyramidal Symptom Rating Scale (ESRS). 15 We are presenting some of these data here, because they pertain to the development of the current version of the ASC.
The 72 subjects who were still compliant with medication were assessed for EPS and related distress at the 1-month follow-up. We compared the frequency of spontaneous reports of side effects with reports of the same side effect as obtained by structured interview. To guard against rater bias, the spontaneous self-report always came before the structured section. We asked patients to quantify the extent of their distress; for this analysis, we used moderately severe or severe as the cut-offs for indicating clinically significant distress.
The results are shown in Figure 1. The data show that a structured side effect assessment is about twice as sensitive as spontaneous report, even for detecting moderately distressing side effects. Figure 1 also shows that akathisia and akinesia are far and away the most distressing EPS side effects. All other parkinsonian side effects combined were mentioned as distressing only one-fourth as often.
There was no significant correlation between subjective distress ratings and concurrent objective findings on the ESRS (r = 0.20 for akinesia NS;r = 0.21 for akathisia, NS; and r = -0.04 for parkinsonism, NS). Distress from tardive dyskinesia was uncommon. Only 2 of the 72 patients were distressed about TD, although approximately 8 patients had a clinical diagnosis of TD. Of the two who reported distress related to TD, only one currently had symptoms of dyskinesia, while the other one was distressed by fear of getting TD in the future.
2. Phase of Illness Effects
In a second analysis of the findings from the same group of patients described above, we compared rates of moderate or severe distress from akathisia and akinesia among patients in the hospital nearing discharge with the same group 1 month post-discharge. We found that the proportion of subjects moderately or severely distressed by akathisia dropped by about 7% (from 26.6% of patients at discharge to 20.2% at 1-month follow-up), whereas those moderately or severely distressed by akinesia increased by about a third (from 15.7% of patients at discharge to 24.7% at 1-month follow-up) (see Figure 2). Our post-hoc explanation for the decrease in the rates of distress associated with akathisia is that it probably has to do with the lowering of doses after patients leave the hospital, combined with some accommodation to this side effect. Distress from akinesia, on the other hand, may increase once patients are out and about in the real-world.
The main theoretical point here is that side effect distress can fluctuate, and the evolution of the distress may be related to other factors besides the actual severity of the side effect itself.
Clinical Implications
The findings described above have a number of clinical implications:
* Patients should be asked directly about distress from side effects because they often do not bring it up on their own.
* Objective findings on physical examination do not correlate with subjective distress, at least for the major EPS side effects.
* Patients experience akinesia and akathisia as much more distressing than the more purely motor manifestations of EPS, such as tremor, rigidity, and dyskinesia.
* The type of EPS that causes the most distress seems to be phase-specific, with distress from akathisia being more of a problem during acute treatment and distress from akinesia being greater during maintenance treatment (Figure 2).
3. Expanding Inquiry to Non-EPS Side Effects
There are substantial differences between the older conventional antipsychotics and the newer atypical antipsychotics, including differences in the side effects they cause and the kinds of subjective distress patients treated with them report. In general, atypical antipsychotics are much less likely to cause EPS than conventional antipsychotics. This is, of course, an over-simplification-conventional antipsychotics have other side effects besides EPS and some atypical antipsychotics can be associated with EPS. From the patient's point of view, however, there is a world of difference between the older first generation antipsychotics and the newer atypical agents. 16
Common and distressing non-EPS side effects from antipsychotics include weight gain, anticholinergic side effects, sedation, sexual dysfunction, and amenorrhea/ galactorrhea. It should be noted that gender effects on distress are much more pronounced with non-EPS side effects than with EPS-related problems. For example, high prolactin levels cause amenorrhea and galactorrhea in women much more frequently than gynecomastia in men. Weight gain also frequently appears to be much more distressing for women than men. In contrast, distress over sexual dysfunction seems to be more frequently reported by men. The usefulness of self-report in rating pharmacological responses to non-EPS side effects was shown in one study in which amantadine was used to treat the neuroendocrine side effects of conventional antipsychotics. Using a self-report measure, patients reported improvements in libido and fewer menstrual complaints when amantadine was added to their antipsychotic regimen. 17 The availability of a self-report measure for non-EPS side effects may help track the effectiveness of pharmacologic interventions for these common problems.
We did a study between 1997 and 1998 on the impact of newer antipsychotics on psychiatric rehabilitation. As part of the baseline assessment, we conducted a subjective side effect distress assessment modeled after the assessments described above, but which also included non-EPS side effects such as weight gain and sexual dysfunction. Subjects were 99 stable outpatients with schizophrenia being treated with either conventional antipsychotics or risperidone. The results of this assessment are shown in Tables 1 and 2.
As shown in the tables, non-EPS side effects of anticholinergic problems, sexual dysfunction, and weight gain seem to be common and distressing. It was clear that these side effects need to be measured in any screening assessment of distressing side effects from antipsychotics. However, it was also clear that distress related to EPS is still very much with us and that EPS cannot be dropped from any side effect measure. These results support the feasibility and potential usefulness of developing an integrated screening measure like the ASC, which is described below.
APPROACHES TO SCHIZOPHRENIA COMMUNICATION (ASC)
Two new scales for evaluating the side effects of antipsychotic medications and the subjective distress associated with them have recently been developed by the Approaches to Schizophrenia Communication (ASC) Steering Group. This group, which is made up of psychiatrists from the United States, Canada, and the United Kingdom, was organized to explore day-to-day clinical treatment issues concerning patients with schizophrenia and to identify areas in which improvements in the standard of care were needed. The two ASC scales were developed in response to the group's perception of a need for tools to improve communication between patients and service providers concerning side effects and patients' subjective experiences of treatment. 18 The C-PET (Checklist for Patients on Endocrine Therapy), 19 a simple 1-page checklist designed for patients with advanced breast cancer, was used as a model for the ASC self-report checklist.
Two versions of the ASC were developed:Cited Here...
* ASC-SR, a self-report checklist to be completed by the patient. It contains a list of common or clinically important side effects of antipsychotics.
* ASC-C, a clinician-administered version of the tool that is designed to be completed by clinician and patient together, forming the basis for a semi-structured interview
The two versions of the ASC have different purposes and can be used in several different ways. The two scales are presented on pages 69-72. The ASC Training Guide for both versions is provided on page 64.
Using the ASC
Self-Report Version. The ASC-SR is a checklist of common problems on which the patient is asked to check only those boxes that apply to him or her; the patient can also check another box if he or she would like to talk to a nurse or doctor about the problem. The patient can complete the ASC-SR in the waiting room before the appointment. The patient then brings the form to the interview session, where it can be reviewed. Because the ASC-SR asks only about common side effects, it is possible to cover all of the checked ASC-SR items during the evaluation. If time is limited, the clinician can focus on the right-hand column of the ASC-SR, where the patient is asked to place a check if he or she would like to speak to a clinician about the problem. Use of the ASC-SR should decrease the time needed to assess for common side effects and it may also help clinicians identify possible side effects that might otherwise have been missed. For example, in testing the ASC-SR, we found that some patients checked the Concerns about sexual functioning item without ever having complained about these same side effects to the clinician, although he knew them well. When asked why they had not discussed their sexual difficulties, the patients said they had been too embarrassed and that it was easier to report this problem on a form, even though they knew that the same clinician would be reading it!
Clinical Interview Version. The ASC-C is designed for mental health clinicians to use as a brief interview for side effects during a regular therapeutic session. One of the major advantages of the ASC-C is that the clinician who administers it does not have to be an expert on psychopharmacology. He or she just needs minimal training concerning the common side effects of antipsychotics and how patients report them (see ASC Training Guide on page 64).
The ASC-C is a screening measure that focuses only on common and bothersome side effects. It does not cover uncommon or medically dangerous side effects, such as neuroleptic malignant syndrome. Therefore, it is appropriate to complete an ASC-C interview and wait for the next routine psychiatric evaluation to do a more in-depth side effect examination. The ASC-C becomes part of the patient's clinical record. If administered by another member of the treatment team, it can be given to the patient's physician to be used in the next psychopharmacological evaluation.
Limitations of the ASC. It is important to keep in mind that the ASC is only a screening form. Patients may check or endorse items on the ASC that, on further evaluation, are not really very bothersome or clinically relevant. Also keep in mind that items listed on the ASC do not necessarily represent side effects. Patients may check or endorse items when they experience problems that are not related to a medication side effect. For example, the underlying problem for a patient checking change in energy might be negative symptoms, not side effects. While the ASC cannot be used to diagnose side effects, it can alert the clinician to areas that seem to need further clinical attention and evaluation.
The ASC has a number of other limitations. There are other potentially serious side effects that are not covered by the ASC. These include acute dystonia, neuroleptic malignant syndrome, urinary retention, and seizures, to name a few examples. Not only are these side effects uncommon, but they would require immediate intervention, which is beyond the purpose of the ASC. It is also important to remember that the ASC does not replace an examination by a psychiatrist or other mental health practitioner qualified to do a side effect assessment. It also cannot substitute for the other standard movement disorder scales, especially the AIMS for the diagnosis of tardive dyskinesia. The ASC is meant to supplement, not replace, these scales.
Case Example. One of the goals of the ASC is to prevent relatively straightforward side-effect problems from deteriorating into a crisis. The following case vignette describing a patient of one of the authors (PJW) illustrates the kind of complication that can occur when a common side effect is disregarded for a long period of time.
Ms. A is a 28-year-old woman who had been taking antipsychotics for over a year. I saw Ms. A every month for routine medication checks at a local community mental health center (CMHC) where I worked one afternoon a week. In that setting, I spent most of my time putting out fires for patients in crisis. Consequently, my time available to spend with Ms. A was quite limited.
Two weeks after Ms. A's last session, I got an urgent call from Ms. A's residence that she was in a crisis. A staff person there said that Ms. A was in a panic and was rushing up and down the hall screaming that she had a brain tumor. I asked the staff member to escort Ms. A to the CMHC for an emergency visit with me.
When I saw her, Ms. A was sobbing and panicky. Eventually, she calmed down enough to tell me that she went to a gynecologist who did a blood test. When the results came back, this doctor told her that she needed more tests to check for a brain tumor. Eventually I figured out that Ms. A went to see the gynecologist because of persistent amenorrhea and deduced that she was about to get a million dollar work-up to rule-out a pituitary adenoma. It seemed to me that this was unnecessary because the cause of the amenorrhea was certainly antipsychotic-induced hyperprolactinemia.
At first, I wished that Ms. A had told me about her amenorrhea, since I might then have been able to prevent this crisis by educating her about this side effect. However, in reviewing Ms. A's records, I found a brief note from a year earlier that Ms. A had already mentioned that her periods had stopped. In my note, I said that I had reassured her that about the amenorrhea being a side effect of her antipsychotic medication. However, both of us had forgotten about this session.
Eventually I was able to reassure Ms. A. I also contacted the gynecologist, who did not know that Ms. A was taking antipsychotic medication. However, I had lost valuable clinical time needed for other patients, and Ms. A had undergone a stressful and frightening experience.
If a screening instrument such as the ASC had been used in such a situation, it might have helped identify and track Ms. A's amenorrhea.
SUMMARY
Distress is a moving target, affected by social expectations, knowledge, and alternative choices. What was acceptable to our patients yesterday may not be acceptable today. Likewise, what is considered an acceptable side effect today may become unacceptable tomorrow. Applying the moving target model to antipsychotics, we note that the EPS caused by conventional antipsychotics were initially thought to be minor and that it took many years to fully understand the terrible burden caused by EPS. The moving target model suggests that, in the future, much more attention will need to be placed on non-EPS side effects. Differences in the side effects caused by the various atypical antipsychotics will therefore become increasingly important in choosing among them. 20
The shift in focus has created a need to take another look at assessing side effects in patients on antipsychotic medications. There is little doubt that just as there is a new generation of antipsychotics, we will need a new generation of side effect measures to help us track the changing side effect problems that are emerging in addition to EPS. The ASC has been developed to help clinicians screen for common EPS and non-EPS side effects in one assessment. It is not diagnostic or comprehensive, but it is quick and requires minimal training. Its development has been the outgrowth of several studies on subjective distress that have tracked changing patterns over the years. We are currently studying the reliability and validity of the ASC in clinical practice. We are conducting studies of interrater and test-retest reliabilities and are testing validity by comparing results from the ASC with those of independently obtained side-effect measures. Hopefully, our data will support our hypothesis that the ASC is a useful tool for improving the recognition and management of the range of side effects experienced by patients on antipsychotic medications.
FOOTNOTES
*Exceptions include the subjective component of the Barnes and other akathisia scales, and the subjective distress item of the AIMS. However, even these scales do not use the subjective component as the primary measure of overall severity of the EPS. Cited Here...
†The development of the ASC program was supported by an unrestricted educational grant from AstraZeneca Pharmaceuticals. Cited Here...
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