A Syndrome of Increased Affect in Response to Risperidone Among Patients With Schizophrenia

Thirteen patients who met DSM-III-R criteria for chronic or subchronic schizophrenia provided written informed consent and participated in a ten-week open trial of risperidone. All of the patients were men.

Patients with schizoaffective disorder were excluded from the study. Other exclusion criteria were treatment resistance, inability to have current antipsychotic medication discontinued, and pregnancy.

For all study patients, the dose of risperidone was titrated to 6 mg over three days. Most stopped their current antipsychotic medication with the beginning of titration. Three patients were rapidly tapered off their previous antipsychotic medication. One patient was not taking an antipsychotic medication at the time of the study. Patients continued taking other medications that had been prescribed for them, including antiparkinsonian agents. No other medications were added during the trial.

The mean age of the subjects was 39.7 years, with a range from 25 to 48 years. Their mean age at onset of psychosis was 20.8 years, with a range from 15 to 28 years. Patients were rated on the Brief Psychiatric Rating Scale (BPRS) and the Scale for Assessment of Negative Symptoms (SANS) (5) at baseline and at ten weeks, for those who completed the study. Ratings on the BPRS and SANS were made by a nontreating clinician who had completed training in use of the instrument and showed good interrater reliability. Ratings of the overall severity of patients' positive, negative, and affective symptoms and their response to risperidone were made by the authors at baseline, two weeks, six weeks, and ten weeks. The Mann Whitney U test was used to evaluate the significance of differences in symptoms between patients who experienced a problematic increase in affect after responding to risperidone and those who did not.

The following case report illustrates the troublesome affect experienced by some patients who responded to risperidone.

Mr. A is a 48-year-old white man with a 24-year history of paranoid schizophrenia. He had chronic delusions of persecution despite taking 35 mg of fluphenazine per day. The patient was started on risperidone 1 mg twice a day, and the dose was titrated up to 3 mg twice a day in three days. The fluphenazine was stopped with the first dose of risperidone because the patient experienced acute urinary retention.

Two weeks after the switch to risperidone Mr. A was much less guarded and showed more affect, joking with the staff. He reported being aware of smiling more but was uncomfortable with this change. A week later he went to his local emergency room, reported paranoia, and was switched back to trifluoperazine, which made him feel more comfortable. When questioned about his symptoms, he reported unpleasant memories of his childhood accompanied by strong affect. This experience made him afraid to go out, which he designated as "paranoid.”

Months later Mr. A agreed to try risperidone again. He was maintained on trifluoperazine 20 mg a day, and 1 mg of risperidone was added. A week later he reported being more social and less paranoid. After two weeks he reported more activity and interests, but he complained of distress related to memories of childhood. He was encouraged to continue the risperidone, and he took 1 mg a day for more than six weeks, but he was virtually immobilized by his emotions, so risperidone was discontinued. He quickly returned to baseline (feeling paranoid, but tolerating that feeling). He subsequently had a trial of olanzapine, which improved his symptoms, but without the distress associated with risperidone.

Follow-up data were available for 12 of the 13 patients who entered the study. One patient left treatment after responding well to risperidone at two weeks. Six of the patients who remained in the study experienced troublesome affect. Symptoms included agitation, crying, insomnia, and depression. The patients complained of unaccustomed affect, especially sadness and anxiety.

We noticed patterns in this response and seemed able to predict which patients would have more difficulty. The most vulnerable were patients who currently or historically had ideas of reference or delusions of being controlled. Patients who had anergia, avolition, and blunted affect seemed to be less vulnerable.

To test these hypotheses, we examined baseline data from the BPRS and SANS. We expected that patients who did not experience this syndrome would have higher scores on the SANS than those who did. However, no difference was found (see Table 1). BPRS scores were higher for patients who showed this effect, but not significantly so. We looked specifically at BPRS subscales that addressed the paranoid subtype—anxiety, grandiosity, suspiciousness, and excitement. Although results on all of those subscales showed a trend toward differentiating the two groups, only scores on the anxiety subscale showed a statistically significant difference. Comparison of a sum of scores on these four subscales for the two groups showed a slightly higher statistical significance.

Our experience suggests that in switching from traditional antipsychotic medications to risperidone, most patients with schizophrenia may experience an enhancement of their ability to feel affect. For some patients, this change is overwhelming and intolerable. One explanation is that increased affect precedes the antipsychotic effect of risperidone, so the affect is interpreted by the patient in a paranoid fashion. However, none of the patients expressed actual paranoia or other psychotic ideation.

For subsequent patients being started on risperidone, we added the medication without decreasing the antipsychotic medication the patient had previously been taking. Nevertheless, troublesome affect was experienced by several patients, including one patient who was taking 48 mg of perphenazine and one patient who was taking 700 mg of clozapine. Both had a good response at two weeks, but shortly thereafter had intolerable symptoms. For one, the symptoms were related to the return of sexual interest; another said that things became "too real.”

Patients with delusions of external control may be more likely to experience this response because their paranoia makes them accustomed to interpreting affect as a danger signal and to responding with distress and hypervigilance. In addition, patients with paranoid schizophrenia tend to remain more cognitively and emotionally intact; other patients may be unable to experience such intense affect after years of illness.

A third possibility is that the phenomenon could represent the resolution of a primary or secondary deficit syndrome. Lewander (6) described patients taking remoxipride who experienced an “awakening”due to amelioration of cognitive, conative, affective, and emotional functions. Lewander attributes these effects to both symptom reduction and an apparent absence of the neuroleptic-induced deficit syndrome. Similar changes have been reported for patients taking clozapine (7,8). These studies report that the time to onset of the changes varies from two months to a year.

Although no doubt the patients in the study reported here experienced a reduction of neuroleptic-induced deficit syndrome, this difference cannot account for the suddenness of the changes we observed, which took place over one to two weeks after starting risperidone. Nor can it account for the changes that were experienced by patients who were taking no antipsychotic medication when risperidone was started, by patients who continued taking a full dose of a traditional antipsychotic medication, or by patients who were taking clozapine.

Certainly, neuroleptic-induced deficit syndrome can be difficult to distinguish from the deficits associated with schizophrenia (9). However, the patients who had few positive symptoms before taking risperidone did not develop intolerable affect, but rather had a gradual resolution of their negative symptoms. The phenomenon of troublesome affect appeared to occur only among patients who had positive symptoms in addition to negative symptoms.

The data reported here suggest that atypical antipsychotic medications may have some distinct effects on patients with schizophrenia. Some patients, especially those with higher levels of anxiety, may have difficulty managing the changes. Further studies are needed to more clearly define the nature of these reactions, management strategies, and implications for the understanding of the biological bases of the symptoms of schizophrenia.

This work was supported by the Janssen Pharmaceutica Research Foundation and by the Veterans Health Services and Research Administration of the Department of Veterans Affairs.

The authors are affiliated with the chronically mentally ill patient care line in the Department of Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way, Mailstop 116MHC, Seattle, Washington 98108. Dr. Ashleigh is also assistant professor in the department of psychiatry and behavioral sciences at the University of Washington in Seattle.