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Association Between Nonpsychotic Psychiatric Diagnoses in Adolescent Males and Subsequent Onset of Schizophrenia
Mark Weiser, MD;
Araham Reichenberg, PhD;
Jonathan Rabinowitz, PhD;
Zeev Kaplan, MD;
Mordehai Mark, MD;
Ehud Bodner, PhD;
Daniella Nahon, MA;
Michael Davidson, MD
Arch Gen Psychiatry. 2001;58:959-964.
ABSTRACT
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Background Nonpsychotic psychiatric symptoms may occasionally herald the later
development of schizophrenia. This study followed a population-based cohort
of adolescents with nonpsychotic, non–major affective psychiatric disorders
to ascertain future hospitalization for schizophrenia.
Methods Results of the medical and mental health assessments on 124 244
16- to 17-year-old males screened by the Israeli draft board were cross-linked
with the National Psychiatric Hospitalization case registry, which contains
data on all psychiatric hospitalizations in the country, during a 4- to 8-year-long
follow-up through age 25 years. In the cohort, 9365 adolescents were assigned
a nonpsychotic, non–major affective diagnosis by the draft board.
Results After excluding 167 adolescents who were hospitalized before or up to
1 year after the draft board assessment, 1.03% of the adolescents assigned
a nonpsychotic, non–major affective psychiatric diagnosis, compared
with only 0.23% of the adolescents without any psychiatric diagnosis, were
later hospitalized for schizophrenia. Of the patients with schizophrenia,
26.8%, compared with only 7.4% in the general population, had been assigned
a nonpsychotic, non–major affective psychiatric diagnosis in adolescence
(overall odds ratio [OR], 4.5; 95% confidence interval [CI], 3.6-5.6), ranging
from OR, 21.5 (95% CI, 12.6-36.6) for schizophrenia spectrum personality disorders
to OR, 3.6 (95% CI, 2.1-6.2) for neurosis.
Conclusion These results reflect the relatively common finding of impaired functioning
in patients later hospitalized for schizophrenia and the relatively low power
of these disorders in predicting schizophrenia.
INTRODUCTION
SEVERAL prospective longitudinal or follow-up studies suggest that some
adolescents who manifest abnormal behavior or personality traits may be at
high risk of manifesting mental illness as adults. Adolescents diagnosed as
having personality disorders are at increased risk for anxiety, disruptive
behavior, affective symptoms, and substance abuse during early adulthood,1, 2 and persons with obsessive-compulsive
disorder, social phobia, and panic attacks examined in the National Institute
of Mental Health Epidemiologic Catchment Area study3
were at increased risk for future schizophrenia. The Minnesota Multiphasic
Personality Inventory traits of depression, anxiety, internalized anger, social
alienation, and withdrawal are associated with increased risk of future schizophrenia.4 Adolescents with schizotypal personality traits seem
to be at a particularly high risk for future psychosis.5, 6, 7, 8
A recent follow-up study of conscripts screened by the Swedish army found
that 18-year-olds with personality disorders, neurosis, substance abuse, or
alcohol abuse were at increased risk for future schizophrenia.9
Similarly, studies of persons with schizophrenia found that some future patients
had subnormal intelligence, withdrawn social behavior, conduct and adjustment
abnormalities, and very mild neurological deficits10, 11, 12, 13, 14, 15
years before the onset of psychosis. Assessing the prevalence of nonpsychotic
psychiatric disorders preceding the diagnosis of schizophrenia is important
in understanding the pathophysiologic characteristics of the illness, as some
authors16, 17 claim that these
abnormalities may reflect a neurodevelopmental origin of illness. In addition,
diagnoses with relatively high rates of later hospitalization for schizophrenia
might constitute part of a cluster of markers to be used in the future for
the early detection of schizophrenia. Such a cluster might include impaired
attention,18 a decrease in the normal inhibition
of the P50 auditory-evoked response to the second of paired stimuli,19 and impaired eye tracking.20
The current study combined data from the mental health screening assessment
performed by the Israeli draft board, with data from the Israel Psychiatric
Hospitalization Registry. The study is unique in that it is based on data
from the complete, nationwide population of male adolescents, and it contains
information on absolutely all psychiatric hospitalizations in the country.
To evaluate the association between manifestation of nonpsychotic, non–major
affective psychiatric disorders in adolescence and later manifestation of
schizophrenia, (1) adolescents with nonpsychotic, non–major affective
psychiatric disorders in adolescence were followed up to ascertain the risk
of hospitalization for future schizophrenia, and (2) the prevalence of nonpsychotic,
non–major affective psychiatric disorders during adolescence was ascertained
in persons diagnosed with schizophrenia. It was hypothesized that nonpsychotic,
non–major affective psychiatric diagnoses, particularly schizophrenia-spectrum
personality disorders (SSPDs) (ie, paranoid or schizotypal personality disorders),
would be more prevalent among future schizophrenic patients compared with
persons not later hospitalized for schizophrenia.
Because subnormal intellectual functioning is present in some persons
with nonpsychotic psychiatric disorders21, 22, 23, 24
and is also a risk factor for schizophrenia,10
the influence of intellectual functioning as a confounding factor for the
risk for schizophrenia in adolescents with nonpsychotic, non–major affective
psychiatric disorders was also assessed.
SUBJECTS, MATERIALS, AND METHODS
SUBJECTS
The study cohort consisted of 124 244 males aged 16 to 17 years
who underwent mandatory medical and psychiatric screening by the draft board.
PSYCHIATRIC ASSESSMENT AT AGE 16 TO 17 YEARS
Draft Board Assessment
Israeli law requires that the entire, unselected population of males
between the ages of 16 to 17 years undergo a preinduction medical and psychiatric
assessment of their eligibility for military service.25, 26
This assessment is performed in regional draft board centers located throughout
the country. The screening procedure includes medical and psychiatric history
conducted by a physician, and intelligence testing, consisting of 4 multiple-choice
subtests testing arithmetic ability, verbal abstraction and concept formation,
visuospatial abilities, and the ability to understand written instructions.
In addition, an interview assessing personality and behavioral traits is administered
by college-aged individuals who participated in a 4-month-long training course
on the administration of the interview. Based on the interview and on findings
from the physician's examination, adolescents who are suspected of having
behavioral disturbances or mental illness are referred for an in-depth assessment
by a mental health professional, and if the adolescent warrants a psychiatric
diagnosis, he is examined by a board-certified psychiatrist. Criteria for
referral to an in-depth mental health assessment include a history of psychological
or psychiatric treatment or complaints, manifestation of behavioral abnormalities
during the physician's examination or psychometrician's interview, or obtaining
the lowest score on the rating of social functioning in the screening interview,
which corresponds to the lowest fifth percentile in the population.
The mental health assessment is a comprehensive psychosocial examination
performed by a clinical social worker or psychologist who inquires about personal
and family history, previous psychological and psychiatric treatments, interpersonal
relationships, self-esteem, self-injurious and antisocial acts, and functioning
within the family and in school. If the clinician suspects that the adolescent
has psychopathologic characteristics, a provisional diagnosis is suggested,
and the adolescent is then referred for evaluation to a board-certified psychiatrist
experienced in treating adolescents. Adolescents who had previously been treated
by mental health professionals, or who had been hospitalized, are required
to present treatment summaries and/or discharge letters. Diagnoses during
the time covered by this study were based on International
Classification of Diseases, Ninth Revision (ICD-9) criteria; however, not all ICD-9 diagnoses
were used during the period covered by this study. Diagnoses were categorized
into 17 major groupings: schizophrenia; schizophreniform disorder; brief reactive
psychosis; organic psychotic disorder; major affective disorder, which includes
affective disorder with or without psychotic features; avoidant and dependent
personality disorders; histrionic personality disorder; obsessive-compulsive
personality disorder; narcissistic or borderline or schizoid personality disorders;
paranoid personality disorder; antisocial personality disorder; neurosis,
which lumps together anxiety, obsessive-compulsive disorder, phobias, chronic
posttraumatic stress disorder, and reactive depression; adjustment disorder;
combat-related acute stress disorder, equivalent to DSM-IV acute stress disorder; alcohol and other drug abuse; and mental retardation.
Although schizotypal personality disorder is not an ICD-9 diagnosis, it was also included in the list of draft board diagnoses
based on the DSM-III-R description, including symptoms
of oddity, unusual perceptual experiences, social isolation, and suspiciousness.
In cases of comorbidity, the examining psychiatrist decides which diagnosis
is most clinically significant, and only that diagnosis is recorded without
the comorbid condition. For the sake of simplicity, personality disorders
were divided into 3 groups: (1) schizophrenia spectrum personality disorders
(schizotypal and paranoid personality disorders), (2) antisocial personality
disorder, and (3) other personality disorders (avoidant, dependent, histrionic,
obsessive-compulsive, narcissistic, borderline, or schizoid personality disorders).
Because this article focuses on the risk for future schizophrenia in adolescents
with nonpsychotic, non–major affective psychiatric diagnoses, adolescents
diagnosed with affective disorders by the draft board were not included in
the analysis, as some of the adolescents with affective disorders had psychotic
as well as affective symptoms. Of the 124 244 male adolescents screened,
9365 were diagnosed with a nonpsychotic, non–major affective psychiatric
disorder.
Hospitalizations for Schizophrenia
The National Psychiatric Hospitalization Case Registry is a complete
listing of all psychiatric hospitalizations in the country, including the
diagnosis assigned and coded on admission and discharge by a board-certified
psychiatrist at the facility. During the time covered by this study, ICD-9 diagnoses were used by the registry. All inpatient
psychiatric facilities in the country, including psychiatric hospitals, day
hospitals, and psychiatric units in general hospitals, are required by law
to report all admissions and discharges to the registry.
The National Psychiatric Hospitalization Case Registry was used to identify
those adolescents screened by the draft board who were later hospitalized
for schizophrenia. From the complete cohort of 124 244 adolescents, during
a follow-up of 4 to 8 years (oldest person at time of follow-up was aged 25
years), a total of 577 males were hospitalized with a diagnosis of schizophrenia,
bringing the risk for schizophrenia in this population to 0.46%, which is
comparable to the age-adjusted incidence of schizophrenia in other studies
carried out in Israel27 and the United States.28, 29
The current analysis focused on those adolescents diagnosed by the draft
board with a nonpsychotic, non–major affective psychiatric disorder
who were later hospitalized for schizophrenia. To underscore the distinction
between the diagnosis of a nonpsychotic psychiatric disorder and the hospitalization
associated with a diagnosis of schizophrenia, all adolescents (n = 167) who
were hospitalized for schizophrenia prior to or within 1 year after the draft
board assessment were excluded from the analysis. Using these criteria, of
9365 adolescents diagnosed with a nonpsychotic, non–major affective
psychiatric disorder by the draft board, 96 (1.03%) were later hospitalized
for schizophrenia. In comparison, 0.23% of the population of adolescents who
did not have a psychiatric diagnosis by the draft board were later hospitalized
for schizophrenia.
STATISTICAL ANALYSIS
The main analyses used odds ratios (ORs) that, in view of the relative
rarity of the outcome (hospitalization for schizophrenia), estimated the desired
incidence rate ratio. The ORs and 95% confidence intervals (CIs) were calculated
using SAS computer software (SAS version 6.12; SAS Institute, Cary, NC).
Subnormal intellectual functioning is present in some persons with nonpsychotic
psychiatric disorders21, 22, 23, 24
and is also associated with future schizophrenia in this population of adolescents
(OR, 2.16; 95% CI, 2.004-3.430) and in other similar populations.12 We therefore asked if subnormal intellectual performance
is a confounding factor for the risk for schizophrenia in adolescents with
nonpsychotic psychiatric disorders. The association between each psychiatric
diagnosis and later hospitalization for schizophrenia was recalculated while
controlling for intellectual performance. In this analysis we applied separate
hierarchical logistic regression models for each of the psychiatric diagnoses.
In each regression model, intellectual performance was entered first, and
the psychiatric diagnosis was entered in the second step.
The risk of hospitalization for schizophrenia for adolescents with different
nonpsychotic psychiatric diagnosis was also a function of the follow-up period;
the longer the follow-up period, the greater the chances of hospitalization
for schizophrenia. To ascertain differences in follow-up periods for different
diagnoses, the mean follow-up time for adolescents with each draft board diagnosis,
or with no draft board diagnosis, were compared using analyses of variance.
RESULTS
The follow-up of adolescents with nonpsychotic, non–major affective
psychiatric diagnoses found that having any nonpsychotic, non–major
affective psychiatric disorder in adolescence increased the risk of future
hospitalization for schizophrenia compared with the risk for schizophrenia
in the entire cohort of adolescents. Table
1 displays the number of adolescents who were assigned nonpsychotic,
non–major affective psychiatric diagnoses by draft board psychiatrists
and the rate of later hospitalization for schizophrenia. The prevalence of
nonpsychotic, non–major affective psychiatric disorders in future schizophrenia
patients was 26.8% compared with 7.4% of nonpsychotic, non–major affective
psychiatric disorders in the general population of adolescents (OR, 4.5; 95%
CI, 3.6-5.6).
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Association Between Nonpsychotic Psychiatric Diagnoses and Later Hospitalization
for Schizophrenia in a Population of 17-Year-Old Males
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An association was found between the different disorders in adolescence
and schizophrenia. The magnitude of this association differed between the
different diagnostic groups. For example, patients with a registry diagnosis
of schizophrenia were approximately 21.5 times more likely to have had a premorbid
diagnosis of SSPD in adolescence compared with the prevalence of SSPD in the
general population of adolescents. On the other hand, patients with a registry
diagnosis of schizophrenia were only about 3.6 times more likely to have had
a premorbid diagnosis of neurosis in adolescence compared with the prevalence
of neurosis in the general population of adolescents.
The mean follow-up period for adolescents with each nonpsychotic psychiatric
diagnosis, or with no draft board psychiatric diagnosis, was significantly
different, the mean follow-up periods ranging from 7.0 to 7.4 years (SD, 1
year) (F7,124 234 = 36.15, P<.001).
Controlling for intellectual functioning decreased the association with future
schizophrenia for most of the nonpsychotic disorders, with the decreases in
OR reaching 65% across the different diagnoses (Table 1).
COMMENT
In this population-based cohort, approximately 26.8% of the males hospitalized
for schizophrenia had nonpsychotic, non–major affective psychiatric
disorders in adolescence compared with a prevalence of 7.4% of nonpsychotic,
non–major affective psychiatric disorders in the general population
of adolescents. These findings are consistent with and expand on previous
studies10, 11, 12, 13, 14, 15
that found that persons with schizophrenia often have behavioral and emotional
disturbances years before the manifestation of psychosis. More unique are
the findings of the follow-up, which found that adolescents with nonpsychotic,
non–major affective psychiatric disorders had an increased risk for
future schizophrenia (1.03%) compared with the risk for schizophrenia in the
entire population (0.46%). Taken together, these may indicate that although
many patients with schizophrenia have behavioral deviations in adolescence,
these behavioral deviations alone, without exploring subjective experience,30, 31 lack the specificity necessary to
predict future schizophrenia.30, 31
This is because most adolescents (approximately 99%) who have nonpsychotic,
non–major affective psychiatric disorders do not later have schizophrenia.
Another singular finding of this report is the gradient of association
between the various psychiatric disorders and future schizophrenia. While
the ORs of persons with other personality disorders and neuroses were 3.6
to 3.9, adolescents with antisocial personality disorder, mental retardation,
or drug abuse had ORs in the range of 7 to 9. Moreover, adolescents with SSPDs
had an OR of 21.5. It could be hypothesized that those nonpsychotic, non–major
affective psychiatric disorders with higher ORs share more genetic or environmental
factors in common with schizophrenia. This makes sense particularly for the
SSPDs, which are phenomenologically more similar to schizophrenia.32
The data presented here are consistent with high-risk studies33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43of
children and siblings of persons with schizophrenia that found increased prevalence
of nonpsychotic symptoms and diagnoses in these persons and increased prevalence
of schizophrenia at follow-up. Furthermore, the finding that adolescents with
SSPDs have increased chances of future schizophrenia replicates and expands
other studies, which found that magical thinking6, 7
and schizotypal symptoms5 increase the risk
of future schizophrenia. Drug abuse also has been reported by others to be
a risk factor for future schizophrenia44, 45;
our finding of alcohol and other drug abuse as significant risk factors (OR,
6.8) is consistent with these findings. The findings in this report replicate
very closely a recently published article with a similar design,9
which followed conscripts screened by the Swedish draft board for future hospitalization
for schizophrenia. That study reports that 38% of the future patients had
a diagnosis of nonpsychotic psychiatric disorder at age 18 years, with ORs
of 4.6 for neurosis, 8.2 for personality disorder, 5.5 for alcohol abuse,
and 14.0 for substance abuse. The great similarity of the findings in that
article with the present report supports the reliability of the data reported
here.
Subnormal intellectual functioning is present in some persons with nonpsychotic
psychiatric disorders21, 22, 23, 24
and is also associated with future schizophrenia in this and other populations12 of adolescents (OR, 2.16; 95% CI, 2.004-3.430). We
therefore controlled for the effect of intellectual performance on the risk
for schizophrenia. We found that when intellectual functioning is controlled
for, the association of nonpsychotic, non–major affective psychiatric
diagnoses with future schizophrenia is decreased by up to 65% across the different
diagnoses. This suggests that although subnormal intelligence confounds the
risk of later hospitalization, having a nonpsychotic, non–major affective
psychiatric diagnosis in adolescence still increases the risk for future schizophrenia
independent of subnormal intelligence.
The follow-up period covered by this study, between 4 to 8 years, is
not long enough to include all cases of future schizophrenia in this cohort;
a longer follow-up period would enable identification of additional cases.
There were slight differences in mean follow-up time between adolescents with
different diagnoses, which might have affected the ORs. However, these differences
were slight, up to 4 months, and are not likely to significantly affect these
results.
The diagnoses assigned by draft board psychiatrists are not research
but clinical diagnoses, raising concerns about their accuracy. However, all
the psychiatrists working for the draft board are board certified, received
their postgraduate education after the introduction of DSM-III, and are instructed and supervised on a regular basis for quality
and consistency. The 3-stage screening procedure used by the draft board dictates
that before the adolescent is referred to the psychiatrist, the interviewer
assessing personality and behavioral traits and the clinical social worker
or clinical psychologist must identify him as having significant behavioral
problems. In addition, the clinical social worker or clinical psychologist
assigns a tentative diagnosis, so that the psychiatric diagnosis assigned
reflects the consensus diagnosis. Disagreements between the two are resolved
by consensus with the help of another senior psychiatrist. This being said,
because the reliability of the ICD-9 is known to
be problematic,46, 47 the comparison
of risks between different diagnostic categories must be regarded as tentative.
The prevalence of nonpsychotic, non–major affective psychiatric
diagnoses made by the draft board in the population of adolescents, approximately
7.4%, is lower than the prevalence of psychiatric disorders found in some,
but not all, other studies; a review48 of the
prevalence of psychiatric diagnoses in children and adolescents living in
the community found a mean prevalence of 15% (range, 1%-51%). One reason for
the relatively low prevalence rates observed may be that the draft board screening
procedure sets a high threshold for diagnosis of minor psychiatric disturbances
compared with screening instruments used in epidemiological surveys. For example,
diagnoses such as specific phobias (included here in the "anxiety" category)
that are relatively common in epidemiological surveys are less common in the
present sample. The prevalence of substance abuse in the population is also
low. This has been reported in a previous study on the epidemiology27 of psychiatric disorders in young adults in Israel,
which also found low prevalence of substance abuse compared with the prevalence
of substance abuse in the United States or Europe. In addition, the differences
in prevalence may be partially explained by the fact that this cohort included
only males, whereas females have, in some but not all studies, a higher rate
of psychiatric disorders.49, 50, 51
However, even if some individuals who merited a diagnosis of nonpsychotic
and non–major affective psychiatric disorders were overlooked, this
does not invalidate the associations reported here.
A related concern is the fact that the case registry diagnoses are clinical,
not research diagnoses. However, these diagnoses too are assigned by board-certified
psychiatrists who have had the benefit of observing the patient throughout
one or more hospitalizations, and have been trained and retrained in the use
of the diagnostic criteria of the ICD-9. Moreover,
studies that have compared clinical diagnoses of schizophrenia assigned in
state hospitals52 with research diagnoses have
shown a high degree of concordance. It is clear that the optimal design of
a study assessing the association between nonpsychotic psychiatric disorders
in adolescence and future schizophrenia would screen subjects using structured
instruments to ascertain diagnoses both of the nonpsychotic psychiatric disorders
and of schizophrenia. However, the incidence of schizophrenia in the population
is between 0.5% and 1%, and not all patients have abnormal personality functioning
before manifesting psychosis. To yield significant results, this hypothetical
protocol would therefore necessitate screening of hundreds of thousands of
adolescents and then following them for years, a project that is probably
not feasible in the near future.
In summary, the results of this study, based on the screening of an
entire population of 16- to 17-year-old males, indicate that nonpsychotic,
non–major affective psychiatric disorders in adolescence are associated
with future schizophrenia. The predictive power of SSPDs in particular, although
significant, is not strong enough to recommend prophylactic treatment with
antipsychotic or other medications. Hence, these data advocate for intensive
research in this area rather than suggesting immediate clinical implications.
Additional studies combining information about genetic, obstetric, and intellectual
risk factors, together with behavioral disturbances in adolescence, may enable
more accurate identification of persons who will later have schizophrenia.
AUTHOR INFORMATION
Accepted for publication March 23, 2001.
From the Sheba Medical Center, Tel-Hashomer (Drs Weiser, Reichenberg,
and Davidson), Bar Ilan University (Dr Rabinowitz), Division of Mental Health,
Mental Health Department, Medical Corps, Israel Defense Forces (Drs Kaplan,
Mark, and Bodner), and Division of Mental Health, Ministry of Health (Dr Mark
and Ms Nahon), Israel.
Corresponding author and reprints: Michael Davidson, MD, Chaim Sheba
Medical Center, Tel-Aviv University, Tel-Hashomer 52621, Israel (e-mail:
davidso{at}netvision.net.il).
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