Professional Documents
Culture Documents
838
839
840
because it provides a means of assessing phenotypic traits of the schizophrenia spectrum that may not be grossly evident clinically [48,49]. It is possible
that vulnerability markers can identify trait-linked abnormalities that are
common to the nonpsychotic schizophrenia spectrum disorders and potentially identify more homogeneous subgroups that are linked to specic pathophysiologic processes [50]. Because these schizophrenia spectrum groups
may have some genetic vulnerability to schizophrenia but do not have many
of the confounding variables (chronic illness, medication eects, and multiple hospitalizations) seen in schizophrenic patients, this research can provide
important information regarding the core decits of schizophrenia spectrum
subjects that are directly related to functional outcome. Since individuals
with SPD do not usually manifest the more generalized decits of chronic
schizophrenia patients, the study of this population may add insight into the
primary (versus generalized) decits of schizophrenia patients.
Vulnerability markers in the schizophrenia spectrum
Abnormalities of attention, cognition, and information processing in
schizophrenia patients have long been recognized [51]. Psychophysiologic
and neuropsychological measures of information processing have been used
to quantify these cognitive abnormalities and may represent vulnerability
markers that are possible endophenotypes for schizophrenia spectrum illness [52]. The neurobiologic measures may assess traits that are tied closer
to brain function than are the clinical diagnostic categories for schizophrenia spectrum illness that probably represent relatively remote and variable
aspects of genes that predispose to schizophrenia [53]. If vulnerability
markers could be used in conjunction with clinical criteria to better identify
individuals who are at risk for developing psychosis (see later section), it
may be possible to intervene early in the course of prodromal schizophrenia
and perhaps prevent some of the devastating eects of the illness.
Measures of central inhibition
Researchers have hypothesized that the observed attention and cognitive
abnormalities of schizophrenia spectrum subjects are secondary to decits
in inhibitory functioning that cause sensory inundation by external and
internal stimuli [55]. Schizophrenia patients, their relatives, and SPD subjects have decits when assessed in various psychophysiologic paradigms,
including prepulse inhibition (PPI) of the startle response [5557], P50
event-related potential suppression [5860], and the antisaccade (AS) task
[6163]. These three tasks have been designed to study central inhibition.
Prepulse inhibition of the startle response
Prepulse inhibition of the startle response is an operational measure of
sensorimotor gating in which weak prestimuli are presented at brief intervals
841
(eg, 100 msec) before a startle-eliciting stimulus, which reduces the magnitude of the response [55,64]. In humans, PPI is quantied by assessing the
reduction in the magnitude of the blink reex component of the startle
response to startle eliciting stimuli versus trials that also include a prepulse
stimulus. PPI is a stable neurobiologic marker with high reliability across
repeated test sessions [65]. Schizophrenia patients [55,6669], SPD subjects
[56,57], and clinically unaected relatives of schizophrenia patients have
reduced PPI [57] when compared to normal comparison subjects, which suggests that PPI is potentially a useful endophenotype in the study of schizophrenia spectrum disorders [70]. The use of nonmedicated SPD subjects is
particularly important because there is some evidence from between-subjects
schizophrenia studies that atypical versus typical neuroleptic treatment may
improve PPI [67,69]. Consistent with the data in patients, in an animal model
of schizophrenia-linked PPI decits, PPI decits induced in rats by apomorphine or phencyclidine (PCP) are reversed by neuroleptic medication [71].
Although the heritability of PPI has not been assessed denitively, aective modulation of the startle response seems to be at least partially under
genetic control because monozygotic (but not dizygotic) twins show similar
changes in startle magnitude in this paradigm [72]. Sibling pairs (one with
schizophrenia, one without schizophrenia) from a recent PPI family study
[57] show relatively high PPI correlations (n 13 pairs, R 0.66), which
adds support to the notion that PPI is a heritable vulnerability trait. Preliminary work has shown evidence of high PPI heritability in mice [73,74], and
Joober et al [75] have reported a series of overlapping quantitative trait loci
mediating startle and PPI in mice, which suggests that mammalian PPI is
under genetic inuence.
P50 event-related potential suppression
In the conditioning-testing P50 paradigm [76], two rapid auditory click
stimuli are presented 500 msec apart and the P50 event-related potential
response to both clicks is assessed. In normal subjects there is suppression
of the second P50 wave that is believed to be related to the activation of
inhibitory processing and circuitry by the rst P50 stimulus. Normal P50
gating is present by late adolescence [77,78]. P50 suppression is a stable trait
[79,80] with high heritability. Schizophrenia patients [48,8183], SPD subjects [58], and relatives of schizophrenia patients [60,84,85] all have reduced
P50 suppression compared to normal comparison subjects. The nding of
P50 suppression decits in SPD subjects and relatives of schizophrenia
patients suggests that the P50 paradigm assesses trait markers for schizophrenia spectrum illness. P50 suppression has been linked with a genetic
marker at the locus of the alpha-7 subunit of the nicotinic receptor in a
study of schizophrenia kindreds [48]. This linkage nding is the rst one
to link a candidate endophenotype of information processing decits in
schizophrenia to a specic chromosomal region. As in the PPI literature,
it seems that atypical antipsychotic medications may at least partially
842
reverse the P50 suppression decits of schizophrenia patients [8689]. Studies of SPD subjects, rst break and nonmedicated schizophrenia patients,
and relatives of schizophrenia patients are essential.
Antisaccade paradigm
The antisaccade task is a measure of saccadic inhibition that requires subjects to look in the opposite direction of a computer-generated cue. Schizophrenia patients, their nonpsychotic rst-degree biologic relatives, and SPD
subjects generate an increased proportion of antisaccade errors [61,63,90].
Poor antisaccade performance correctly identied 70% of schizophrenia
patients and 25% to 50% of these patients nonpsychotic rst-degree relatives in three samples [91].
Convergence and divergence across inhibitory measures
in schizotypal subjects
In a recent study [92], the question was asked whether the decits in
inhibition observed in SPD subjects on measures of PPI, P50, and antisaccade are present in all SPD subjects or if distinct subgroups of SPD subjects
can be identied on the basis of their performance on these measures. The
authors also questioned whether it was possible to dene an endophenotype
using measures of inhibitory functions within a population of SPD subjects
for use in future genetic studies [70]. The results of this study suggest that the
inhibitory decits measured by the P50 and antisaccade paradigms are signicantly correlated and are present in a signicant subgroup of subjects
with SPD, whereas the PPI paradigm seems to identify a distinct subgroup
of subjects. The relationship between P50 and antisaccade performance has
been reported in schizophrenia patients and their relatives, and a composite P50/AS phenotype has been linked to a marker on chromosome 22q
in these families [93]. The use of multiple neurobiologic measures that dene
separate phenotypes and diering neural substrates within schizophrenia
spectrum populations also may provide a means of reducing the heterogeneity characteristic of clinically dened samples. When compared with
clinically dened phenotypes, neurobiologic measures also may assess specic brain function more directly and provide simpler, empirically derived
phenotypes.
The convergence and divergence in performance on the various measures
of inhibitory functioning suggest that there may be overlap in the modulatory neural circuitry responsible for central inhibition on the three tasks.
There also may be important dierences in SPD subjects performance that
may provide insight into separate neurophysiologic substrates that are
implicated in schizophrenia spectrum disorders. Further work using animal
models, functional neuroimaging, or brain mapping may provide clues to the
similar and diering inhibitory functions. Vulnerability markers could be
843
used not only in genetic analyses [70] but also as predictive variables in studies of individuals at risk for the later development of psychotic illness [94].
Prodromal schizophrenia: the study of individuals at risk for psychosis
Schizophrenia is a devastating disease that often emerges during late adolescence or early adulthood, a crucial phase of psychological and social
development. Although many treatments for schizophrenia are eective,
they are also limited and palliative. The idea of intervening in the prodromal
stages of schizophrenia has been advocated for more than 70 years [95].
Clinical research has shown that the longer the duration of untreated psychosis, the poorer the treatment response, which suggests that early intervention may greatly improve the outcome of the illness [94,96,97]. It is
also possible that if intervention occurs before the onset of decit symptoms
and cognitive decline, these processes can be prevented or respond to current
treatments [94,98]. The use of vulnerability markers along with clinical symptoms and genetic risk may help researchers to improve the predictive power
of identifying individuals at risk for schizophrenia for early intervention.
Most research into the symptoms that precede the rst episode of schizophrenia has been retrospective in nature, reconstructing the prodromal
changes reported by schizophrenic patients and their relatives [99101]. In
a literature review that outlined the observed stages of psychosis, Docherty
[100] described early stages in which the person becomes overwhelmed easily
and withdraws socially (overextension and restricted consciousness). The
disinhibition stage, characterized by symptoms such as ideas of reference,
may follow a transition event in which decompensation may be promoted. Psychotic disorganization is the stage in which cognitive disorganization may be prominent along with the development of hallucinatory
phenomena. The nal stage of psychotic resolution includes prominent psychotic organization with the development of an organized delusional system
and denial of illness.
Most studies have noted prodromal periods to last anywhere from a few
days to 5 years [99101]. The symptoms most often reported in the early
stages of the prodrome include reduced concentration and attention,
reduced drive and motivation, anergia, depressed mood, sleep disturbance,
anxiety, social withdrawal, suspiciousness, deterioration in role functioning,
and irritability [102]. Many prodromal symptoms are nonspecic in nature,
but it has been suggested that certain symptoms, such as disturbance of
selective attention, perceptual abnormalities, and other attenuated forms
of psychotic symptoms, have some specicity for psychosis [103105].
Davidson et al [106] reported that decits in social functioning, organizational ability, and intellectual functioning were the strongest predictors of
schizophrenia in a group of Israeli men who received draft board tests and
were later hospitalized for schizophrenia. In further analysis of the draft
board study, Weiser et al [107] report that adolescents with a schizophrenia
844
845
role functioning) of at-risk mental states are vague and nonspecic and lead
to a high incidence of false-positive results in their preliminary studies, only
symptoms with specicity for the development of psychosis were used [102].
The state group included individuals who had attenuated forms of psychotic symptoms, including at least one of the following symptoms: ideas
of reference, odd beliefs or magical thinking, perceptual disturbance, odd
thinking and speech, paranoid ideation, odd behavior or appearance (from
DSM-IV criteria for schizotypal personality disorder). The symptoms had
to occur with a frequency of at least several times per week, and the change
in mental state had to be present for at least 1 week. Individuals who had
transient psychotic symptoms (hallucinations, delusions, thought disorder)
that resolved within 1 week were also included in the state group.
The second strategy was a modication of the genetic high-risk approach
[113] that involved combining trait-risk factors for psychotic disorders with
state-risk factors. They chose family history of any psychotic disorder or
SPD in any rst-degree relative, as a trait marker, combined with the presence of an at-risk mental state. In this group, at-risk mental states also could
include anxiety or depression as long as it was of sucient severity or duration to indicate a marked deterioration in functioning. Yung et al [102] also
included the risk factor of age by including individuals between age 16 and
30 who are at maximum risk of becoming psychotic. These strategies for
selecting subjects were used to maximize the risk of transition to psychosis
within a short time to study the process in detail. The outcome measure
in this study was the development of psychosis. Yung et al [102] noted that
selecting the exact onset point for psychosis is dicult and must be dened
arbitrarily. In their study, the presence of hallucinations, delusions, or formal thought disorder at least several times per week for longer than 1 week
was dened as psychosis onset consistent with the criteria outlined by
Larsen et al [114].
During the rst 16 months of their study, Yung et al [102] received 119
referrals. Most of their referrals came from primary care physicians, school
counselors, and youth workers and from education of the general public
about the program. Subjects were excluded from participation if they did
not speak English, had a previous psychotic episode of longer than a week
(treated or untreated), or had previous treatment with a neuroleptic for
3 weeks or longer (precluding the ability to detect transition to psychosis).
Seventy-three of the original 119 referrals were not excluded and attended
the appointment. Of those, 49 met intake criteria and 24 did not. Those
individuals who met intake criteria were followed in the PACE clinic, which
is located in a primary care setting that promotes the health of adolescents.
The site of the PACE clinic was chosen to avoid the stigmatizing eects of
being seen in a psychiatric facility. All subjects were oered clinical service
and research involvement. The clinical component included such things
as supportive therapy, relaxation training, and monitoring for impending
psychosis. Neuroleptic agents were used in one case that demonstrated a
846
high suicide risk, but in general the initial approach to treatment with
medication was more conservative than that described by Falloon et al [115].
Yung et al [102] were mindful of ethical issues when dealing with this
population. In the PACE clinic they did not emphasize the risk of transition
to psychosis or schizophrenia because they did not know what the risk or
transition rate was and they did not want to prematurely stigmatize or
worry the patients and their families. The need for intervention was explained in terms of the presenting problems. Of the rst 20 people recruited
into the study, 8 (40%) became psychotic within the rst 6 months. In a
recent presentation of clinical trial data, McGorry et al [116] reported that
of 60 patients who met criteria for at-risk mental states, 32 were assigned to
a treatment group who received ripseridone, 1 to 2 mg/d, antidepressants,
and anxiolytics in combination with cognitive behavioral therapy. The control group of 28 patients received basic support, antidepressants, and anxiolytic medications. 12.5% of the treatment group and 36% of the control
group converted to psychosis.
The Cologne Early Recognition Project included outpatients who were
examined with the Bonn Scale for the Assessment of Basic Symptoms to
identify individuals in the schizophrenia prodrome. This prospective study
included 110 patients with and 50 without prodromal symptoms. At follow-up, 79 patients (77 who had had prodromal symptoms and 2 who had
not) had developed schizophrenia. Although the sensitivity (0.98) and the
negative predictive (0.96) values were high, the specicity (0.59) and positive
predictive values (0.7) of prodromal symptoms were lower, and the false
positive rate was 20.6%. When specic criteria from the Bonn scale were
analyzed, thought interference, disturbances of receptive language, and visual distortions were able to predict schizophrenia with a probability up to
91%, with false-positive rates between 1.9% and 7.5%.
The studies by Falloon, McGorry, and Yung [102,109,110] and recent
programs developed by McGlashan [94], Tsuang [98], Larsen [117], and
Cornblatt [108] demonstrate the feasibility of identifying individuals in the
community at risk for psychosis. Preliminary data from the various sites
report that 30% to 40% of the at-risk population converts to psychosis within the rst few years [118]. The development of these programs provides education to primary care providers, teachers, and school counselors about the
prodromal forms of mental illness. These studies also demonstrate that it
may be possible to intervene earlier in the course of schizophrenia and prevent some of the devastating eects of the illness.
The CARE (Cognitive Assessment and Risk Evaluation) program was
established at University of California, San Diego, in 2000. The primary aim
of the CARE program is to identify and assess adolescents and young adults
between the ages of 12 and 30 who are experiencing changes in their
thoughts, behavior, or emotions that might put them at risk for developing
schizophrenia. Individuals who have low-grade psychotic symptoms or meet
criteria for schizotypal personality disorder are included, as are individuals
847
Summary
A continuum of symptoms between normality and overt psychosis has
been documented in relatives of schizophrenia patients, SPD, and individuals who may be in the early stages of a psychotic illness with subsyndromal symptoms. The empirically derived criteria for SPD have been
rened to dene a clinical phenotype that is linked to schizophrenia. The
clinical SPD symptoms dene a heterogeneous group of individuals who are
often comorbid for Axis I and II disorders, may or may not have a family
history of schizophrenia, and are at risk for developing schizophrenia themselves. SPD subjects have similar abnormalities to those observed in schizophrenia patients on various psychophysiologic paradigms designed to study
central inhibition, including P50 event-related potential suppression, PPI of
the startle response, and the antisaccade task. Because SPD subjects do not
have many of the confounding variables observed in schizophrenia patients
(ie, medication eects), these paradigms might represent vulnerability markers that are possible endophenotypes for schizophrenia spectrum illness.
Questions still remain as to whether SPD is genotypically linked to
schizophrenia but has genes of lesser penetrance, fewer aected genes, lack
of a second hit, or perhaps protective factors. It is also possible that SPD,
like schizophrenia, is a common nal pathway that can come about because of several etiologic factors that aect crucial neurodevelopmental periods. Future directions in SPD work might include the use of vulnerability
markers to essentially subtype schizophrenia spectrum patients and create
simpler endophenotypes to understand the phenomenologic and neurobiologic substrate. The use of vulnerability markers along with clinical symptoms may help to improve the predictive power for identifying individuals
848
at risk for schizophrenia for early intervention. Finally, genetic studies have
yet to be performed in SPD.
References
[1] Bleuler E. Dementia praecox; or, the group of schizophrenias. Monograph series on
schizophrenia; no. 1. New York: International Universities Press; 1964.
[2] Kendler KS, Gruenberg AM, Kinney DK. Independent diagnoses of adoptees and
relatives as dened by DSM-III in the Provincial and national samples of the Danish
adoption study of schizophrenia. Arch Gen Psychiatry 1994;51:45668.
[3] Kety S, Wender P, Jacobsen L, Ingraham L, Jansson L, Faber B, et al. Mental illness in
the biological and adoptive relatives of schizophrenic adoptees: replication of the
Copenhagen study in the rest of Denmark. Arch Gen Psychiatry 1994;51:44255.
[4] Kraepelin E. Dementia praecox: the clinical roots of the schizophrenia concept.
Translations of seminal European contributions on schizophrenia. Cambridge (UK):
Cambridge University Press; 1987. p. 1324.
[5] Rosano A. A study of heredity in insanity in light of the mendelian theory. American
Journal of Insanity 1911;1:21134.
[6] Deutsch H. Some forms of emotional disturbance and their relationship to schizophrenia.
Psychoanal Q 1944;11:30121.
[7] Hoch PH, Cattell JP. The diagnosis of pseudoneurotic schizophrenia. Psychiatr Q 1959;
33:1743.
[8] Knight RP. Borderline states. Bull Menninger Clin 1953;17:12.
[9] Kretschmer E. Die rolle der vererbung und der konstitution in der aetiologie der seelischen
stoerungen. Nederlandsch Tijdschrift voor Psychologie 1938;5:388400.
[10] Rado S. Dynamics and classication of disordered behavior. Am J Psychiatry 1953;110:
40626.
[11] Meehl PE. Schizotaxia, schizotypy, schizophrenia. Am Psychol 1962;17:82738.
[12] Kety SS, Rosenthal D, Wender PH, Schulsinger F. Mental illness in the biological and
adoptive families of adopted schizophrenics. Am J Psychiatry 1971;128:3026.
[13] Kendler KS, Walsh D. Schizotypal personality disorder in parents and the risk for
schizophrenia in siblings. Schizophr Bull 1995;21:4752.
[14] Grinker R, Werble B, Drue R. The borderline syndrome. New York: Basic Books, Inc;
1968.
[15] Kernberg O. Borderline personality organization. J Am Psychoanal Assoc 1967;15:64185.
[16] Spitzer RL, Endicott J, Gibbon M. Crossing the border into borderline personality
and borderline schizophrenia: the development of criteria. Arch Gen Psychiatry 1979;36:
1724.
[17] Gunderson JG, Singer MT. Dening borderline patients: an overview. Am J Psychiatry
1975;132:110.
[18] George A, Solo PM. Schizotypal symptoms in patients with borderline personality
disorders. Am J Psychiatry 1986;143:2125.
[19] Pope HG, Jonas JM, Cohen BM, Lipinski JF. Failure to nd evidence of schizophrenia in
rst-degree relatives of schizophrenic probands. Am J Psychiatry 1982;139:8268.
[20] Keefe RS, Silverman JM, Siever LJ, Cornblatt BA. Rening phenotype characterization
in genetic linkage studies of schizophrenia. Soc Biol 1991;38:197218.
[21] Siever LJ, Gunderson JG. The search for a schizotypal personality: historical origins and
current status. Compr Psychiatry 1983;24:199212.
[22] Siever LJ, Kalus OF, Keefe RS. The boundaries of schizophrenia. Psychiatr Clin North
Am 1993;16:21744.
[23] Kendler KS, Ochs AL, Gorman AM, Hewitt JK. The structure of schizotypy: a pilot
multitrait twin study. Psychiatry Res 1991;36:1936.
849
850
[46] Siever LJ, Silverman JM, Horvath TB, Klar H, Coccaro E, Keefe RS, et al. Increased
morbid risk for schizophrenia-related disorders in relatives of schizotypal personality
disordered patients. Arch Gen Psychiatry 1990;47:63440.
[47] Silverman JM, Siever LJ, Horvath TB, Coccaro EF, Klar H, Davidson M, et al.
Schizophrenia-related and aective personality disorder traits in relatives of probands
with schizophrenia and personality disorders. Am J Psychiatry 1993;150:43542.
[48] Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A, et al.
Linkage of a neurophysiological decit in schizophrenia to a chromosome 15 locus. Proc
Natl Acad Sci USA 1997;94:58792.
[49] Hyman SE. The NIMH perspective: next steps in schizophrenia research. Biol Psychiatry
2000;47:17.
[50] Siever LJ. Brain structure/function and the dopamine system in schizotypal personality
disorder. In: Raine A, Lencz T, Mednick SA, editors. Schizotypal personality. New York:
Cambridge University Press; 1995. p. 27286.
[51] Venables P. Input dysfunction in schizophrenia. In: Maher B, editor. Progress in experimental personality research. New York: Academic Press; 1964. p. 141.
[52] Bra DL. Psychophysiological and information processing approaches to schizophrenia.
In: Charney DS, Nestler E, Bunney BS, editors. Neurobiological foundation of mental
illness. New York: Oxford University Press; 1999. p. 25871.
[53] Tsuang MT. Recent advances in genetic research on schizophrenia. J Biomed Sci 1998;5:
2830.
[54] Bra DL. Information processing and attention dysfunctions in schizophrenia. Schizophr
Bull 1993;19:23359.
[55] Bra DL, Grillon C, Geyer MA. Gating and habituation of the startle reex in
schizophrenic patients. Arch Gen Psychiatry 1992;49:20615.
[56] Cadenhead K, Geyer M, Bra D. Impaired startle prepulse inhibition and habituation
in schizotypal personality disordered patients. Am J Psychiatry 1993;150:18627.
[57] Cadenhead KS, Swerdlow NR, Shafer K, Diaz M, Bra DL. Modulation of the startle
response and startle laterality in relatives of schizophrenia patients and schizotypal personality disordered subjects: evidence of inhibitory decits. Am J Psychiatry 2000;157:
16608.
[58] Cadenhead K, Light G, Geyer M, Bra D. P50 event-related-potential sensory
gating decits in schizotypal personality disordered subjects. Am J Psychiatry 2000;
157:559.
[59] Clementz B, Geyer M, Bra D. Poor P50 suppression among schizophrenia patients
and their rst-degree biological relatives. Am J Psychiatry 1998;155:16914.
[60] Waldo MC, Carey G, Myles-Worsley M, Cawthra E, Adler LE, Nagamoto HT, et al.
Codistribution of a sensory gating decit and schizophrenia in multi-aected families.
Psychiatry Res 1991;39:25768.
[61] Brenner CA, McDowell JE, Cadenhead KS, Clementz BA. Saccadic inhibition among
schizotypal personality disorder and schizophrenia subjects. Psychophysiology 2001;38:
399403.
[62] Katsanis J, Kortenkamp S, Iacono WG, Grove WM. Antisaccade performance in patients
with schizophrenia and aective disorder. J Abnorm Psychol 1997;106:46872.
[63] Ross RG, Harris JG, Olincy A, Radant A, Adler LE, Freedman R. Familial transmission
of two independent saccadic abnormalities in schizophrenia. Schizophr Res 1998;30:
5970.
[64] Kumari V, Soni W, Mathew VM, Sharma T. Prepulse inhibition of the startle response
in men with schizophrenia: eects of age of onset of illness, symptoms, and medication.
Arch Gen Psychiatry 2000;57:60914.
[65] Cadenhead KS, Carasso B, Swerdlow NR, Geyer MA, Bra DL. Prepulse inhibition and
habituation of the startle response are stable neurobiological measures in a normal male
population. Biol Psychiatry 1999;45:3604.
851
[66] Grillon C, Ameli R, Charney DS, Krystal J, Bra D. Startle gating decits occur across
prepulse intensities in schizophrenic patients. Biol Psychiatry 1992;32:93943.
[67] Kumari V, Soni W, Sharma T. Normalization of information processing decits in
schizophrenia with clozapine. Am J Psychiatry 1999;156:104651.
[68] Nuechterlein KH, Dawson ME. Information processing and attentional functioning in
the developmental course of schizophrenic disorders. Schizophr Bull 1984;10:160203.
[69] Weike AI, Bauer U, Hamm AO. Eective neuroleptic medication removes prepulse
inhibition decits in schizophrenia patients. Biol Psychiatry 2000;47:6170.
[70] Cadenhead K, Bra DL. Enophenotyping schizotypy: a prelude to genetic studies within
the schizophrenia spectrum. Schizophr Res 2002;54:4757.
[71] Swerdlow NR, Bra DL, Taaid N, Geyer MA. Assessing the validity of an animal model
of decient sensorimotor gating in schizophrenic patients. Arch Gen Psychiatry 1994;51:
13954.
[72] Carlson SR, Katsanis J, Iacono WG, McGue M. Emotional modulation of the startle
reex in twins: preliminary ndings. Biol Psychol 1997;46:23546.
[73] Bullock AE, Slobe BS, Vazquez V, Collins AC. Inbred mouse strains dier in the regulation
of startle and prepulse inhibition of the startle response. Behav Neurosci 1997;111:
135360.
[74] Paylor R, Crawley JN. Inbred strain dierences in prepulse inhibition of the mouse startle
response. Psychopharmacology (Berl) 1997;132:16980.
[75] Joober R, Zarate JM, Rouleau GA, Skamene E, Boksa P. Quantitative trait loci modulating the acoustic startle response and prepulse inhibition of acoustic startle. Society for
Neuroscience Proceedings 2001 (abstract).
[76] Adler LE, Pachtman E, Franks RD, Pecevich M, Waldo MC, Freedman R. Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in
schizophrenia. Biol Psychiatry 1982;17:63954.
[77] Freedman R, Adler LE, Waldo M. Gating of the auditory evoked potential in children
and adults. Psychophysiology 1987;24:2237.
[78] Myles-Worsley M, Coon H, Byerley W, Waldo M. Developmental and genetic inuences
on the P50 sensory gating phenotype. Biol Psychiatry 1996;39:28995.
[79] Boutros NN, Overall J, Zouridakis G. Test-retest reliability of the P50 mid-latency
auditory evoked response. Psychiatry Res 1991;39:18192.
[80] Waldo MC, Graze K, de Gra Bender S, Adler LE, Freedman R. Premenstrual mood
changes and gating of the auditory evoked potential. Psychoneuroendocrinology 1987;12:
3540.
[81] Clementz BA, Geyer MA, Bra DL. P50 suppression among schizophrenia and normal
comparison subjects: a methodological analysis. Biol Psychiatry 1997;41:103544.
[82] Freedman R, Adler LE, Waldo MC, Pachtman E, Franks RD. Neurophysiological evidence for a defect in inhibitory pathways in schizophrenia: comparison of medicated and
drug-free patients. Biol Psychiatry 1983;18:53751.
[83] Judd LL, McAdams L, Budnick B, Bra DL. Sensory gating decits in schizophrenia:
new results. Am J Psychiatry 1992;149:48893.
[84] Siegel C, Waldo M, Mizner G, Adler LE, Freedman R. Decits in sensory gating in
schizophrenic patients and their relatives: evidence obtained with auditory evoked
responses. Arch Gen Psychiatry 1984;41:60712.
[85] Young D, Waldo M, Rutledge J, Freedman R. Heritability of inhibitory gating of the P50
auditory-evoked potential in monozygotic and dizygotic twins. Neuropsychobiology 1996;
33:1137.
[86] Light GA, Geyer MA, Clementz BA, Cadenhead KS, Bra DL. Normal P50 suppression
in schizophrenia patients treated with atypical antipsychotic medications. Am J Psychiatry
2000;157:76771.
[87] Nagamoto HT, Adler LE, Hea RA, Grith JM, McRae KA, Freedman R. Gating of
auditory P50 in schizophrenics: unique eects of clozapine. Biol Psychiatry 1996;40:1818.
852
[88] Nagamoto HT, Adler LE, McRae KA, Huettl P, Cawthra E, Gerhardt G, et al. Auditory
P50 in schizophrenics on clozapine: improved gating parallels clinical improvement
and changes in plasma 3-methoxy-4- hydroxyphenylglycol. Neuropsychobiology 1999;39:
107.
[89] Yee CM, Nuechterlein KH, Morris SE, White PM. P50 suppression in recent-onset
schizophrenia: clinical correlates and risperidone eects. J Abnorm Psychol 1998;107:
6918.
[90] Fukushima J, Morita N, Fukushima K, Chiba T, Tanaka S, Yamashita I. Voluntary
control of saccadic eye movements in patients with schizophrenic and aective disorders.
J Psychiatr Res 1990;24:924.
[91] McDowell JE, Myles-Worsley M, Coon H, Byerley W, Clementz BA. Measuring liability
for schizophrenia using optimized antisaccade stimulus parameters. Psychophysiology
1999;36:13841.
[92] Cadenhead K, Light G, Geyer M, McDowell J, Bra D. Neurobiological measures in
schizotypal personality disorder: beginning to dene a phenotype? Am J Psychiatry
2002;159:86971.
[93] Myles-Worsley M, Coon H, McDowell J, Brenner C, Ho M, Lind B, et al. Linkage
of a composite inhibitory phenotype to a chromosome 22q locus in eight Utah families.
Am J Med Genet 1999;88:54450.
[94] McGlashan TH. Early detection and intervention of schizophrenia: rationale and
research. Br J Psychiatry 1998;172(Suppl):36.
[95] Sullivan HS. The onset of schizophrenia. Am J Psychiatry 1994;151:1359.
[96] Lieberman JA, Alvir JM, Woerner M, Degreef G, Bilder RM, Ashtari M, et al.
Prospective study of psychobiology in rst-episode schizophrenia at Hillside Hospital.
Schizophr Bull 1992;18:35171.
[97] Vaglum P. Earlier detection and intervention in schizophrenia: unsolved questions.
Schizophr Bull 1996;22:34751.
[98] Tsuang MT, Stone WS, Seidman LJ, Faraone SV, Zimmet S, Wojcik J, et al. Treatment
of nonpsychotic relatives of patients with schizophrenia: four case studies. Biol Psychiatry
1999;45:14128.
[99] Beiser M, Erickson D, Fleming JA, Iacono WG. Establishing the onset of psychotic
illness. Am J Psychiatry 1993;150:134954.
[100] Docherty JP, Van Kammen DP, Siris SG, Marder SR. Stages of onset of schizophrenic
psychosis. Am J Psychiatry 1978;135:4206.
[101] Hafner H. Onset and course of the rst schizophrenic episode. Kao Hsiung I Hsueh Ko
Hsueh Tsa Chih 1998;14:41331.
[102] Yung AR, Phillips LJ, McGorry PD, McFarlane CA, Francey S, Harrigan S, et al.
Prediction of psychosis: a step towards indicated prevention of schizophrenia. Br J
Psychiatry 1998;172(Suppl):1420.
[103] Bowers MB Jr, Freedman DX. Psychedelic experiences in acute psychoses. Arch Gen
Psychiatry 1966;15:2408.
[104] Chapman J. The early symptoms of schizophrenia. Br J Psychiatry 1966;112:22551.
[105] Klosterkotter J, Hellmich M, Steinmeyer EM, Schultze-Lutter F. Diagnosing schizophrenia in the initial prodromal phase. Arch Gen Psychiatry 2001;58:15864.
[106] Davidson M, Reichenberg A, Rabinowitz J, Weiser M, Kaplan Z, Mordehai M.
Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. Am J Psychiatry 1999;156:132835.
[107] Weiser M, Reichenberg A, Rabinowitz J, Kaplan Z, Mark M, Bodner E, et al. Association
between nonpsychotic psychiatric diagnoses in adolescent males and subsequent onset of
schizophrenia. Arch Gen Psychiatry 2001;58:95964.
[108] Cornblatt B, Obuchowski RS, Goldman RS, Bergman A, Smith C, Baruch-Feldman C,
et al. This Hillside RAPP Clinic: intervention during the schizophrenia prodrome. Biol
Psychiatry 1998;43:84S.
853
[109] Falloon IR, Coverdale JH, Laidlaw TM, Merry S, Kydd RR, Morosini P. Early
intervention for schizophrenic disorders: implementing optimal treatment strategies in
routine clinical services. OTP Collaborative Group. Br J Psychiatry 1998;172(Suppl):338.
[110] McGorry P. Preventive strategies in early psychosis: Verging on reality. [editorial]. Br J
Psychiatry 1998;172(Suppl):12.
[111] McGlashan TH. Early detection and intervention in schizophrenia: editors introduction.
Schizophr Bull 1996;22:1979.
[112] McGorry PD, Edwards J, Mihalopoulos C, Harrigan SM, Jackson HJ. EPPIC: an evolving
system of early detection and optimal management. Schizophr Bull 1996;22:30526.
[113] Cornblatt B, Obuchowski M. Update of high-risk research: 19871997. Int Rev Psychiatry
1997;9:43747.
[114] Larsen TK, McGlashan TH, Moe LC. First-episode schizophrenia: I. Early course
parameters. Schizophr Bull 1996;22:24156.
[115] Falloon IR. Early intervention for rst episodes of schizophrenia: a preliminary exploration. Psychiatry 1992;55:415.
[116] McGorry P, Phillips L, Yung A, Francey S, Velakoulis D, Brewer W, et al. The
identication of predictors of psychosis in a high risk group. Schizophr Res 1999;36:
4950.
[117] Larsen T, Joa I. Identifying persons prodromal to rst episode schizophrenia: the TOPPOrihect. Curr Opin Psychiatry 1999;12:207.
[118] Larsen TK, Friis S, Haahr U, Joa I, Johannessen JO, Melle I, et al. Early detection and
intervention in rst-episode schizophrenia: a critical review. Acta Psychiatr Scand 2001;
103:32334.