Phenylthiocarbamide Perception in Patients With Schizophrenia and First-Degree Family Members

Forty-two patients with schizophrenia (30 men and 12 women), 23 healthy volunteers (11 men and 12 women), and 12 first-degree relatives (four men and eight women) were recruited from the University of Pennsylvania Schizophrenia Research Center. The relative cohort included one parent, eight siblings, and three adult offspring of six patients. The patients received the Structured Clinical Interview for DSM-IV, Patient Edition (11), a physical examination, and routine laboratory tests. The patients were rated on the Brief Psychiatric Rating Scale (BPRS) (12), the Scale for the Assessment of Negative Symptoms (13), and the Scale for the Assessment of Positive Symptoms (14). Family members were assessed with the Structured Clinical Interview for Personality Disorders (15). All probands met DSM-IV criteria for schizophrenia with no other concurrent diagnoses. Family members and healthy comparison subjects were free of any current axis I diagnosis or axis II cluster A personality disorder.

Subjects were excluded for a history of neurological disorder, head trauma, loss of consciousness, substance abuse/dependence, a medical condition that might alter cerebral functioning, a recent respiratory infection, or any condition that could affect taste functioning. Written informed consent was obtained after a complete description of the study was given to the subjects.

There were no differences in age among the patients (mean=36.7, SD=12.7), family members (mean=41.2, SD=18.8), and healthy comparison subjects (mean=30.8, SD=12.8) (F=2.5, df=2, 74, p=0.09). The probands had a greater proportion of African Americans than the healthy comparison subjects (χ²=12.8, df=6, p<0.05). All patients were stable outpatients at the time of testing. Mean duration of illness was 11.8 years (SD=8.6). Twenty-five patients were receiving atypical antipsychotic medications, six were receiving typical antipsychotics, and 11 were unmedicated at the time of testing. The mean dose was 323.3 mg/day (SD=213.6) in chlorpromazine equivalents. The mean BPRS score was 30.4 (SD=8.6), indicating a low level of acute symptoms.

A PTC-impregnated strip of filter paper (Carolina Biological Supply Company, Burlington, N.C.) was placed on the tongue. The subjects were asked if they tasted anything. They were then asked to rate the intensity on a 100-mm visual analog line, ranging from 0 mm (no taste) to 100 mm (extremely strong taste). Any subject who reported an inability to taste the filter paper and an intensity of less than 6 mm was classified as a nontaster. The 6-mm value denoted the break point in the bimodal distribution of intensity ratings between the tasters and nontasters.

Statistical analysis revealed significant differences in the distribution of tasters and nontasters among the three groups (χ²=8.30, df=2, p<0.02), with both patients (χ²=7.53, df=1, p=0.006) and family members (χ²=4.70, df=1, p=0.03) having a larger proportion of nontasters than healthy volunteers (Figure 1). Patients and family members did not differ from one another (χ²=0.01, df=1, p=0.94). Among tasters, there were no group differences in intensity ratings and no effect of diagnosis, sex, or diagnosis-by-sex interaction (all p>0.18).

Within the patient group, tasters and nontasters did not differ in sex distribution, Mini-Mental State Examination (MMSE) score, age at onset, illness duration, illness severity, deficit status, or negative symptoms. The two subgroups did differ in positive symptom ratings (F=5.3, df=1, 33, p<0.03), with nontasters demonstrating higher total scores on the Scale for the Assessment of Positive Symptoms. This reflected higher ratings for the hallucinations (F=7.6, df=1, 33, p=0.009) and delusions (F=5.3, df=1, 33, p<0.03) subscales. Linear regression analyses with age, sex, chlorpromazine equivalents, age at onset, illness duration, smoking history, and MMSE score as predictors did not alter the observed differences in taster status or affect PTC intensity ratings.

These data demonstrate a higher prevalence of PTC nontasters among patients with schizophrenia and their non-ill first-degree relatives. Among healthy comparison subjects, 78% were classified as tasters, in contrast to 43% among patients and 42% among family members. The higher prevalence of nontasters in the patient and family groups is consistent with three other reports of nontaster prevalences ranging from 42% to 47% among patients with schizophrenia (6–8). A higher prevalence of nontasters in patients could not be explained by a greater proportion of African Americans because this ethnic group shows a lower prevalence of nontasters than other populations (4). The presence of a similar impairment in first-degree relatives suggests that people with at least one dominant allele may be at a lower risk than those with two recessive alleles. The high frequency of nontasters in patients and family members may be due to abnormalities in the function and/or expression of G-protein signaling pathways. Drayna and colleagues (16) found that PTC binds to both forms of the receptor (i.e., taster and nontaster) with equal affinity, but the nontaster form fails to activate G-protein. This failure in G-protein signaling may interact with other genetic and/or environmental factors to produce an increased vulnerability to illness. This hypothesis requires further investigation.

A few caveats must be noted. First, the group of family members was relatively small, and a larger cohort will be required to fully assess this difference. However, it is notable that the effect size (Cohen’s d) for the difference in taster status between family members and healthy comparison subjects is quite large (d₊=0.81, 95% confidence interval [CI]=0.08–1.53), and we would expect this effect to be robust in independent samples. Second, the comparison subject group was smaller than the group of patients. Nevertheless, the observed proportions of tasters and nontasters in the healthy group were consistent with other population-based investigations of PTC sensitivity (4).

We conclude that PTC nontaster status may be an endophenotypic marker of an inherited neuronal abnormality that conveys risk for the development of schizophrenia.

Received Feb. 22, 2004; revision received May 4 and May 17, 2004; accepted May 26, 2004. From the Schizophrenia Research Center, Department of Psychiatry, and the Smell and Taste Center, Department of Otorhinolaryngology, Head and Neck Surgery, University of Pennsylvania School of Medicine. Address correspondence and reprint requests to Dr. Moberg, Brain-Behavior Laboratory, Department of Psychiatry, 10th Floor, Gates Bldg., University of Pennsylvania School of Medicine, 3400 Spruce St., Philadelphia, PA 19104; [email protected] (e-mail). Funded in part by NIH grants MH-63381 (to Dr. Moberg), MH-59852 (to Dr. Turetsky), MH-66121, MH-42191 (to Dr. Gur), and an Independent Investigator Award from the National Alliance for Research on Schizophrenia and Depression to Dr. Moberg. The authors thank Ms. Janice Lieber and Mrs. Constance Lieber for their support.