Depressive Symptoms in the Early Course of Schizophrenia: Relationship to Familial Psychiatric Illness

Several measures of probands' symptoms were derived from data of the longitudinal study. The DSM-III-R symptoms of depression and mania were rated during the index psychotic episode with a version of the Present State Examination (PSE) (16) that was expanded to assess the full range of symptoms for the Research Diagnostic Criteria (RDC) (17) and DSM-III-R diagnoses of major affective disorders and schizophrenia. Following didactic instruction and practice interviews, interrater agreement was examined for ratings of nine videotapes of PSE interviews and of one live interview. The average percent agreement on individual symptoms rated present by the PSE trainer, who served as the criterion rater, was 88%. The average percent agreement for individual symptoms rated absent was 94%.

A dichotomous variable of “inpatient depression” was created by dividing the probands into two groups according to whether or not they met DSM-III-R criterion A (sufficient depressive symptoms) for a major depressive episode. All patients who showed inpatient depression according to this criterion had nonetheless been diagnosed as having DSM-III-R schizophrenia, as opposed to DSM-III-R schizoaffective disorder, because the affective symptoms were judged not to have played a prominent role in the overall psychotic episode. An affective syndrome was judged not to be prominent if it was brief relative to the total duration of psychotic symptoms during the episode. Also taken into consideration were the severity of the affective symptoms and whether pharmacologic agents were being used to treat the mood disturbance.

Since these probands had an average of only one manic symptom at the inpatient assessment, and none met the criteria for a DSM-III-R manic episode, manic symptoms were not examined.

The expanded Brief Psychiatric Rating Scale (BPRS) (18) was used every 2 weeks to assess symptom levels of the 70 outpatients. The ratings on the BPRS were done by UCLA Aftercare Research Program staff, who were distinct from the UCLA Family Members Study staff and who were blind to the diagnoses of family members made by the latter staff. The BPRS raters completed intensive, specialized training using videotaped and live interviews (19). They were required to show a median intraclass correlation with criterion ratings of at least 0.80 across items. The BPRS was administered every 2 weeks during the first outpatient year after stabilization of the patient on the standard starting dose of 12.5 mg of fluphenazine decanoate injected every 2 weeks. (Fifty-nine of the 62 DSM-III-R schizophrenic patient probands who completed the approximately 1-year follow-through period were administered the standard starting dose of 12.5 mg of fluphenazine decanoate every 2 weeks throughout most of the 1-year assessment period. Adjustments to this dosage, either upward or downward, were made in eight of these cases according to clinical need during the 1-year assessment period. Three patients were initially stabilized on somewhat lower doses because of uncomfortable side effects. Two patients were administered adjunctive antidepressant medication throughout the 1-year period, and another patient received antidepressant medication as well as lithium during the assessment year.)

A longitudinal 1-year index of depression was calculated for each proband by averaging the ratings on the expanded BPRS item “depressed mood” over the 1-year period. Sixty-two probands had an average of 21.5 (SD=3.9) separate BPRS administrations, covering approximately 43 weeks. The longitudinal depression index was not calculated for eight probands who had insufficient follow-through data. (These eight patients were administered the standard starting dose of 12.5 mg of fluphenazine decanoate at the beginning of the assessment period.) The patients were also grouped according to whether they experienced a clinically significant depressive period during the first outpatient year, as identified by BPRS criteria that paralleled those developed for significant psychotic exacerbation or relapse periods during the 1-year follow-through study phase (8). A clinically significant depressive period was defined on the basis of ratings on the BPRS items of depressed mood, guilt, and suicidality. A significant depressive period after the absence of depressive symptoms involved 1) a rating of 5 (on a scale of 1–7) on one of the three items plus a 2-point increase on one of the other two items on any BPRS covering a 2-week period, 2) a rating of 5 on any of the three items for more than two consecutive 2-week BPRS periods, or 3) a rating of 6 or 7 on any one of these three items on any BPRS covering a 2-week period. A significant depressive period after persistent low-level depressive symptoms was defined as an increase to a rating of 6 or 7 points plus a 2-point increase on one of the other two depressive items. Changes in antipsychotic or antidepressant medication during this period were made on the basis of clinical considerations and were not contingent on these BPRS depression criteria.

We attempted to interview directly all first-degree relatives aged 15 years or older. The interviewers were two doctoral-level clinical psychologists, two doctoral candidates in clinical psychology, and one master's-level research assistant with 10 years' experience in psychiatric research. The Modified DIS/PSE, which consists of a modified National Institute of Mental Health (NIMH) Diagnostic Interview Schedule (DIS) (20) supplemented by additional PSE probes and ratings for psychotic symptoms, was used to assess the major RDC psychiatric diagnoses for the directly interviewed relatives. The RDC were used for axis I disorders for family members because they allow a subdivision of schizoaffective disorder into types that appear to be genetically related to schizophrenic and affective disorders. Thus, these subtypes could be assigned to the schizophrenia or affective disorder family history loadings used in this study (21). For the UCLA Family Members Study, we modified the DIS to include a time line for affective and psychotic syndromes to aid in diagnostic decision making. These modifications ensured that all information necessary for determining RDC and DSM-III-R diagnostic status was elicited. Although the DIS has been used in a variety of epidemiologic studies and has been found to have good reliability and validity (22, 23), our modifications were made to offset some concern about the sensitivity of this instrument for diagnosing schizophrenia. The use of the structured DIS interview ensured that no areas of psychopathology were overlooked, and the semistructured additional PSE probes and syndrome time line facilitated differential diagnosis of schizophrenia, schizoaffective disorder, and affective disorders. Also, only clinically skilled interviewers with additional specialized training in structured psychiatric interviewing were used.

The interviewers were trained to criterion level on the DIS by the same individual who trained the Los Angeles staff of the Epidemiologic Catchment Area project (24). The training involved an intensive initial workshop, rating of sample DIS videotapes, “mock” interviews with friends and relatives, and, finally, interviews with adult inpatients and nonpatient volunteers. The interviewers were trained in PSE administration by the staff of the Diagnosis and Psychopathology Unit of the UCLA Clinical Research Center for Schizophrenia, who also trained the interviewers of the probands.

The Structured Clinical Interview for DSM-III-R Personality Disorders (SCID-II) (25) was used to assess five personality disorders, including two putative schizophrenia-spectrum disorders (paranoid and schizotypal). The training procedures and reliability assessment methods in the current study have been described elsewhere (26). Audiotapes of 45 interviews were rated by separate interviewers to evaluate interrater reliability. Adequate interrater reliability, based on dimensional syndrome scores, was demonstrated for both paranoid and schizotypal personality disorders (intraclass correlations were 0.70 and 0.73, respectively), as well as for the three other personality disorders assessed in the relatives (26). Reliable assessment of paranoid and schizotypal personality disorders has also been previously demonstrated with the SCID-II (27).

Family history information on all first- and second-degree relatives (including directly interviewed relatives) was obtained from two adult informants in each family, usually the parents of the proband. Following the systematic generation of a genealogy diagram, family history information about major psychiatric illnesses was obtained with use of the NIMH Relative Psychiatric History Checklist Interview format (E.S. Gershon, unpublished). This format involved screening questions for the major psychiatric disorders, as well as added screening questions for the five personality disorders of interest. Any positive responses to these screening questions were followed up with more detailed probing. To keep the informant's task manageable, the screening questions were repeated separately for different sibships or for no more than 10 relatives at any one time. For these family history interviews, personality disorders were assessed with the SCID-II sections adapted to a third-person format.

As this investigation was part of a larger ongoing study involving diagnostic interviews with family members of probands with bipolar affective disorder, adult-onset schizophrenia, childhood-onset schizophrenia, attention deficit disorder, or no mental disorder, it was possible to keep the family interviewers blind to the proband's diagnosis. Typically, and whenever feasible, each first-degree relative was interviewed by a staff member who had not interviewed any of the other first-degree relatives within the same family. Since more than one individual covered in the family history interview might be assigned a psychiatric diagnosis, the diagnoses of relatives were by necessity sometimes made with knowledge of diagnoses assigned to other relatives (but not the proband) within the same genealogy. Information regarding other family members' psychiatric histories was not considered in making a family member's psychiatric diagnosis. To minimize further any potential bias in diagnostic judgments, the final consensus diagnosis of each family member who had any psychotic or quasipsychotic symptoms was made through a case presentation of all symptom information to the senior clinicians (K.H.N., R.F.A., and D.L.F.), who were blind to the diagnoses of the probands and all other family members.

Consensus diagnoses were made at two levels. The first level was a consensus based on family history information from two family members and used the Family History RDC (FH-RDC) (28) for the major clinical syndromes and DSM-III-R criteria for the personality disorders. Since the second-degree relatives were not directly interviewed, this first level of consensus diagnosis was the one used for these individuals. The second consensus level was derived from consideration of the family history and direct interview information, as well as psychiatric records if available, and was based on the regular RDC for the major clinical disorders and the DSM-III-R criteria for personality disorders. When direct interview information was available, the diagnoses from the second consensus level were used in the analyses. When direct interview information was not available, first-level consensus diagnoses were used in order to allow each first-degree relative to be represented. At both levels, discrepancies among raters or among the sources of information were reconciled in a meeting with senior investigators in which all decision makers were kept blind to the proband's diagnosis.

Family loadings were computed for each family for three groups of disorders: 1) unipolar-SAAD disorders (RDC definite or probable major depressive disorder; FH-RDC major depressive disorder; and RDC or FH-RDC schizoaffective disorder, mainly affective, depressed subtype); 2) bipolar-SAAM disorders (RDC or FH-RDC manic disorder; and RDC or FH-RDC schizoaffective disorder, mainly affective, manic subtype); and 3) schizophrenia-spectrum disorders (RDC or FH-RDC schizophrenia; RDC or FH-RDC schizoaffective disorder, mainly schizophrenic subtype; DSM-III-R paranoid personality disorder; and DSM-III-R schizotypal personality disorder).

To compute the family psychiatric history loadings, the rates of the three classes of disorders were first age-adjusted within each family for first- and second-degree relatives separately by using the Weinberg shorter method (29). For lifetime morbid risk rates we used 15–39 years as the ages of risk for schizophrenia and schizophrenia-spectrum disorders and 15–59 years for all affective disorders. Individuals whose ages were within the ranges of the ages of risk contributed 0.5 to the denominator or Bezugsziffer (BZ), whereas relatives past the age of risk and individuals affected with the disorder in question contributed 1.0 to the BZ. To take the degree of genetic relationship between each relative and the proband into consideration in calculating a family psychiatric history loading, the morbid risk for the first-degree relatives in a family was multiplied by 0.50, which corresponds to the proportion of shared genes for a parent and proband and the average proportion of shared genes for the siblings. Similarly, the family morbid risk for the second-degree relatives was multiplied by 0.25, which corresponds to the average proportion of their shared genes. These two weighted morbid risk values were then summed to obtain the family loading. Thus, each family contributed three separate scores, one for each dimension of family psychiatric history loading. On infrequent occasions an individual received both a schizophrenia-spectrum diagnosis and an affective disorder diagnosis. For the purposes of the data analyses, these individuals were included in family loading calculations for both diagnostic categories. A natural log transformation of the family loading variables was used to normalize the distributions.

Statistical analyses were completed through four linear regression and logistic regression analyses in which the unipolar-SAAD family psychiatric history loading was used as the predictor variable. The bipolar-SAAM family history loading was not used as a predictor because there were insufficient cases of these disorders in the first- and second-degree relatives. If a significant predictive effect was observed for unipolar-SAAD family loading, the analytic plan was to rerun the regression analysis, forcing in the schizophrenia-spectrum disorder family loading first in order to assess the predictive value of the unipolar-SAAD family loading over and above that which could be accounted for by the variance associated with a schizophrenia-spectrum family history. When the two dimensions were included to evaluate the contribution of a family loading for unipolar affective disorder in the context of the schizophrenia-spectrum loading variable, only the affective disorder family history loading variables were hypothesized to predict affective features in probands. Therefore, the statistical tests for the unipolar-SAAD predictor rather than the overall model are the focus of interest (30).

Because the interpretation of multiple regression analyses that use predictor variables showing high intercorrelations can be complicated, the correlation of the two family loading dimensions (unipolar-SAAD and schizophrenia-spectrum disorders) was computed to determine whether this would be a source of difficulty. The correlation was significant but quite low (Pearson's r=0.28, N=70, p<0.03), indicating some nonindependence of these two family loading dimensions but not enough to compromise the interpretation of the multiple regression analyses.