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ABSTRACT
It has been
postulated that to have any liability for schizophrenia, one must inherit
a particular genetic constitution called “schizotaxia”, which is a ‘subtle
neurointegrative deficit’. Upon this deficit, by the process of social
learning, all individuals with schizotaxia develop a personality
structure, called schizotype. Schizotype is characterized by four traits,
cognitive slippage, social aversiveness, anhedonia and ambivalence.
Schizotaxia was recently reformulated as emerging from the effects of an
early environmental insult in conjunction with a genetic predisposition to
schizophrenia, and schizotype as only one of its possible outcomes. The
concept of schizotaxia several practical implications - the treatment of
non-psychotic relatives of schizophrenia patients could serve to attenuate
clinically meaningful symptoms, while identification of accurate
predictors for development of schizophrenia in these individuals might
enable the prevention of onset of schizophrenia. This review outlines the
evolution of the concept of schizotaxia; its clinical features (including
negative symptoms, psychosocial and neuropsychological impairments,
neurological, neuroanatomic and neurochemical abnormalities), and the
treatment options.
INTRODUCTION
The search for
predictors of schizophrenia has been a major area of research for many
decades, especially so in the relatives of schizophrenia patients.
Conversely, the search for covert neuropsychological and
electrophysiological abnormalities in relatives of schizophrenic patients
has generated much interest. The most interesting concept arising out of
this research is schizotaxia, originally proposed by Meehl (1962).
Schizotaxia is a subtle syndrome of brain dysfunction expressed, in part,
as negative symptoms and neuropsychological deficits, but not as
psychosis. This syndrome is qualitatively similar, yet less severe, than
that observed in schizophrenia patients.
EVOLUTION
OF THE CONCEPT
In 1962, Meehl
postulated that to have any liability for schizophrenia, one must inherit
a particular genetic constitution, which he christened “schizotaxia”. He
hypothesized that a dominant single gene (with reduced clinical
penetrance) specific for schizophrenia interacts with polygenic
potentiators like excessive anxiety, low hedonic capacity, etc. to
predispose one to the illness. He postulated that ‘clinical schizophrenia’
as such cannot be inherited because it has behavioral and phenomenal
contents which are learned, and that what is inherited is a ‘subtle
neurointegrative deficit’, i.e. schizotaxia. This neurointegrative deficit
is ubiquitous - it is something wrong with very single nerve cell at all
levels from the sacral cord to the frontal lobes. Upon this deficit, by
the process of social learning all individuals with schizotaxia develops a
personality structure, which he called the schizotype. Schizotype is
characterized by four traits, cognitive slippage (mild thought disorder),
social aversiveness, anhedonia and ambivalence. He also conjectured that
only a minority of schizotypal individuals decompensate into clinical
schizophrenia. If the interpersonal regime is favorable and if the
individual has also inherited certain constitutional strengths like high
threshold for anxiety and stress, he will remain a well-compensated
schizotype without symptoms of mental disease, but exhibiting faint signs
of “cognitive slippage” and other minimal neurological aberrations. A
minority, disadvantaged by additional (largely polygenically determined)
constitutional weaknesses and by history of poor social learning
influenced by schizophrenogenic mothers (most of whom are themselves
schizotypes), develop schizophrenia. Meehl also postulated that
schizotaxia is a necessary precondition for development of schizophrenia-
nonschizotaxic individuals, lacking the integrative neural defect, will
not become schizotypes and can never manifest its decompensated form,
schizophrenia. At the worst they can develop character disorders,
psychoneuroses or other psychoses like manic depressive disorder.
In a
reformulation, Meehl (1989) postulated the concept of” “hypokrisia”, the
endophenotype produced by the schizotaxic gene. Hypokrisia refer to a
slight quantitative aberration in the synaptic control over the spiking of
a neuron, which leads to aberrations in acquiring, retaining and
generalizing positive and negative social conditionings. He also revised
that schizotaxia need not progress into either schizotype or
schizophrenia, if given well-managed prophylaxis. He postulated that a
generalized quantitative deficiency of Central Nervous System inhibition
function underlines molar schizotaxia. In his initial articles he
maintained that anhedonia is the key symptom of schizotypy, but he later
gave more emphasis to “associative loosening” and “aversive drift”. The
term schizotypy (in the form of schizotypal personality disorder)
eventually entered the diagnostic nomenclature, but schizotaxia did not.
Although the concept of a liability to schizophrenia has retained a
conceptual use with researchers for four decades, schizotaxia was not
associated with specific symptoms or syndromes.
Based on the
neurodevelopmental models of schizophrenia, schizotaxia was recently
reformulated as emerging from a combination of multiple genes and
consequences of early adverse environmental experiences like obstetric
complications (Tsuang et al., 2001). Schizotaxia was proposed to manifest
with clinical and neuropsychologic symptoms; remaining a stable syndrome
in many individuals, affecting approximately 20% to 50% of the adult,
nonpsychotic relatives of schizophrenia patients (Faraone et al.,
1995a,b). An operational research definition of schizotaxia was also
proposed, thus allowing the concept to be validated or disproved
experimentally (Tsuang et al., 1999). This reformulation differed from
Meehl’s original concept in that schizotaxia was suggested to have
clinical phenotype other than schizotypy and that etiology of schizotaxia
was not considered to be exclusively genetic.
CLINICAL
FEATURES OF SCHIZOTAXIA
Meehl (1962) had
assumed that all schizotypes will display some evidence, albeit sometimes
subtle, of their underlying liability in the form of aberrant
psychobiologic, psychological or psychosocial functioning. This feature of
Meehl’s model had guided nearly 40 years of research directed at
developing methods for the valid and efficient detection of schizotaxia
through clinical, psychometric or other means. Converging evidence
supports the view that schizotaxia is a meaningful, clinical condition (Faraone
et al., 2001).
Negative
Symptoms
Relatives of
schizophrenic patients are at high risk for social isolation,
interpersonal dysfunction, impoverished affective experiences and negative
symptoms (especially flat affect and avolition); but not positive symptoms
(Gunderson et al., 1983; Tsuang and Faraone, 1991). Psychometric
assessments of schizotypal symptoms among relatives of patients with
schizophrenia have also revealed a predominance of negative rather than
positive symptoms (Grove et al., 1991). In the Roscommon family study, odd
speech, social dysfunction, and negative symptoms strongly discriminated
relatives of schizophrenia patients from controls (Kendler et al., 1995).
Psychosocial Dysfunction
Psychosocial
dysfunction has been documented among the children of schizophrenia
patients. A recent study using the Copenhagen 1962 HR project revealed
that the adolescent males later diagnosed with schizophrenia were more
likely to pose discipline problems, to disturb the class, to be
emotionally reactive and easily excited, to have been treated by a school
psychologist and to be lonely and rejected by their peers; and that the
female counterparts were more high-strung, less likely to react to praise,
more shy, more excitable, less spontaneous, more passive, more likely to
be rejected by peers and judged more likely to develop future psychiatric
problems. Specific school behaviors taken as aggregate had greater
predictive power than individual school behaviours (Olin et al., 1995).
Studies have shown children of schizophrenia patients to be more
withdrawn, shy, passive, socially isolated, less socially competent, more
aggressive and unlikable by peers (Hans et al., 1992; Ledingham, 1990);
adolescents who have a parent with schizophrenia to show poor social
adjustment (Hans et al., 2000); and child relatives of schizophrenia
patients to demonstrate poor social functioning and restricted interests
(Small, 1990). A review by Asarnow (1988) concluded that all studies of
adolescent relatives have found them to be having significant social
dysfunction. Adult relatives of schizophrenia patients have been found to
have deficits in the social perception of nonverbal cues (Cannon et al,
1990; Toomey et al, 1998).
Neuropsychological Impairments
There is strong
evidence of impairment in sustained attention, perceptual motor speed, and
concept formation in relatives of schizophrenia patients (Cornblatt and
Keilp, 1994; Erlenmeyer‑Kimling et al., 1982; Asarnow et al., 1978).
Impairments in mental control/ encoding, verbal memory, verbal fluency,
binaural listening, and backward masking have also been reported (Cornblatt
and Erlenmeyer – Kimling, 1985; Keefe et al., 1992; Green et al., 1997).
The pattern of deficits parallel that found in schizophrenia patients;
suggesting a dysfunction in prefrontal, temporal, limbic and attentional
systems. When Faraone et al. (2000) divided their sample into simplex (one
schizophrenic relative) and multiplex (two schizophrenic relatives)
groups, the multiplex sample showed a poorer performance in several
domains. Significantly lower scores on abstraction, verbal memory and
auditory attention; and significant intercorrelations among these
functions, have been detected in first-degree relatives of schizophrenia
patients, raising the possibility that multiple risk indicators may help
us better identify relatives carrying the schizophrenia genotype (Toomey
et al, 1998). A reexamination of first-degree, nonpsychotic relatives who
were evaluated four years previously revealed the stability of
neuropsychologic deficits over time (Faraone et al., 1995a,b; Faraone et
al., 1999).
Some studies have
linked the neuropsychological and psychosocial dysfunctions. Auerbach et
al., (1993) detected motor abnormalities in socially withdrawn children.
Rating videotapes of children who later developed schizophrenia, Walker
and Lewine (1990) reported both neuropsychological impairments (poor fine
and gross motor coordination) and evidence of social dysfunction (poor
eye-contact, more negative affect and low social responsiveness). In the
New York high risk project, attentional problems in childhood predicted
social dysfunction in adolescence and social isolation in adulthood (Dworkin
et al, 1993). Chen et al. (1998) showed that deficits in cognition
(ie, sustained attention) were more associated with negative and
disorganized symptoms of schizotypy than they were with positive symptoms
in nonpsychotic relatives. Future confirmation of these causal links would
suggest that treatment of neuropsychological deficits might improve the
psychosocial functioning of schizotaxic individuals.
Neurologic
Abnormalities
Fish (1987)
suggested that neurointegrative deficits, termed pandysmaturation,
involving motor or visual motor skills; during infancy were related to
later appearance of schizophrenia spectrum disorders. Poor motor
coordination was probably the most consistently reported risk factor
distinguishing high risk from low risk children. Impaired motor ability
presents in these children as soft neurological signs such as disturbed
gait, poor balance, incoordination, motor impersistence and impaired
mirror drawing (Mednick and Silverton, 1988). In contrast, motor
functioning has been less consistently impaired among adult relatives of
schizophrenia patients (Kinney et al., 1991; Faraone et al., 1995a). Eye
tracking dysfunction has been shown to aggregate in biological relatives
of schizophrenia patients (Levy et al., 1994).
Structural
Brain Abnormalities
Abnormalities in
limbic-diencephalic areas (ie, thalamus, amygdala, left hippocampus
anterior cingulate, paracingulate cortex, insula, and parahippocampal
gyrus), and prefrontal structures (including the frontal operculum, left
and right medial prefrontal cortex, and left-frontal-middle gyrus), have
been detected in schizotaxia (Tsuang et al, 2003).
Abnormalities in Event Related Potentials
Schreibar et al.
(1989) detected prolonged N2 and P3b latencies in children at risk for
schizophrenia. Though P3 amplitude reduction and latency prolongation have
been detected in schizophrenia proband sample, the finding is inconsistent
(Squires‑Wheeler et al., 1993; Blackwood et al., 1991). Duggal and Nizamie
(2001) reported abnormalities in “bereitschaftspotential” in first-degree
relatives of schizophrenia patients.
Neurochemical Indicators
Growth hormone
response to apomorphine has been reported to differentiate the relative
risk of finding schizophrenia spectrum disorders in the first-degree
relatives of probands (Scutter et al, 1987), and increased cerebrospinal
fluid 5-Hydroxy Indole Acetic Acid levels have been associated with the
genetic risk for schizophrenia (Sedvall et al, 1980).
Glucose
Dysregulation
Mukherjee (1989)
reported elevated rates of non-insulin dependent diabetes in the relatives
of patients with schizophrenia. Stone et al. (2004) found some preliminary
support for the view that genes that regulate glucose metabolism may also
influence susceptibility to schizophrenia.
Thought
Disorder
A metaanalysis of
studies examining psychometrically assessed “thought disorder” in the
relatives of schizophrenics concluded that “thought disorder” is more
prevalent in them than in control subjects (Romney, 1990). McConaghy
(1989) hypothesized that allusive thinking (“loosening” of thinking) is a
trait marker predisposing to schizophrenia, and that concrete thinking is
a state marker. The thought disorder observed among relatives is never as
severe as that seen in schizophrenia patients; but it shares qualitatively
similar characteristics such as looseness of associations, autistic logic,
word finding difficulties, perseveration, and conceptual disorganization.
Changes in
Psychophysiology
Electrodermal
activity (EDA) continues to be a major field of interest in
schizophrenia-risk research, though the problems of nonspecificity and
heterogeneity still beset the field (Claridge, 1994). Both EDA
hyperresponding and hyporesoponding have been shown to characterize
high-risk children (Mednick and Schulsinger, 1973). One interpretation is
that EDA hyperresponding may predict positive symptom schizophrenia and
negative aspects may be linked to hyporesponding to EDA (Cannon et al,
1990). Another paradigm that seems to be of considerable potential in risk
research is prepulse inhibition (Geyer and Braff, 1987).
TREATMENT
OPTIONS FOR SCHIZOTAXIA
The features of
schizotaxia raise two distinct questions for treatment. First, can we
alleviate the negative symptoms, neuropsychological impairment and social
dysfunction of schizotaxia? Second, can we prevent schizophrenia in
schizotaxic adolescents?
Treating
adult schizotaxia
Psychosocial management: The treatment of
schizotaxia may benefit from methods effective in the psychotherapy of
other neurodevelopmental conditions (eg. Adult ADHD) which share some
clinical features with schizotaxia. There are various issues to be
attended in treating patients with subtle neuropsychological impairments (Seidman,
1994).
Firstly, the
therapist should have an objective understanding of the patient’s
neuropsychological strengths and weaknesses. This knowledge helps patients
and significant others to reformulate their view of the behavioral
consequences of cognitive dysfunction. For e.g., schizotaxics with
deficits in attention and verbal memory may view themselves as stupid
because they cannot learn in many educational settings that require these
skills. Therapy can help them reinterpret these difficulties and develop
coping strategies, and might help them develop realistic expectations and
better plan their occupational and educational pursuits.
Secondly,
clinicians could help schizotaxic people develop cognitive behavioral
strategies to cope with specific deficits. For e.g., persons with memory
deficits could benefit from learning mnemonic strategies, using tools like
calendars to aid recall etc, and those with abstraction deficits could be
taught systematic methods of planning and organizing their activities.
Finally,
therapists can use neuropsychological information to facilitate an
empathic approach to the issues of shame, inferiority and performance
anxiety that often arise in patients with neurocognitive disorders. Such
maladaptive emotions may stem directly from the experiences of the failure
caused by the schizotaxic neuropsychological syndrome, may be reactions to
the stress and stigma of having a relative with schizophrenia, or may
derive from the relative’s fear of developing schizophrenia. Without
therapeutic attention, these emotional consequences might worsen cognitive
performance and lead to a downward spiral toward further dysfunction.
Pharmacological management: As schizotaxia
shares causal and pathophysiological components with schizophrenia, it is
assumed that atypical antipsychotics, treating negative symptoms and
improving neuropsychological function may be promising for the treatment
of schizotaxia. Although toxicity of clozapine precludes its use in the
absence of clear psychotic symptoms, the post clozapine agents-
risperidone, olanzapine, and quetiapine may all improve negative symptoms
in patients and risperidone appears to improve some neurocognitive
deficits (Marder and Meibach, 1994; Beasely et al., 1996; Small et al.,
1997). A treatment study of four adult first degree relatives of
schizophrenics who met criteria for schizotaxia reported that all four
cases showed a reduction in negative symptoms and improvement in tests of
attention after six weeks of treatment with risperidone at a dose range of
0.25-2.0 mg per day (Tsuang et al., 1999). A very cautions approach to
this potential use of antipsychotics is warranted, given reports of
spontaneous dyskinesias in schizotypal subjects and widespread
neurological abnormalities in nonpsychotic relatives of patients with
schizophrenia (Kinney et al., 1991; Cassady et al., 1998).
TREATMENT
OF SCHIZOTAXIC ADOLESCENTS
Adequate
management of adolescents diagnosed with schizotaxia is likely to serve
the purpose of primary prevention of schizophrenia in them. A reasonably
accurate ability to predict who will develop schizophrenia is a necessary
precondition for prevention trials. Theoretically, psychosocial
interventions could choose two foci for intervention - The ‘at risk’
person might be helped to withstand the stressful situations that are
inherent in life; or family interventions might reduce stressors that
affect vulnerable family members (Faraone et al, 1995). In addition, the
possibility that psychopharmacologic approaches might improve the stress
tolerance of ‘at risk’ persons should also be considered. Further research
is needed to create a scientific foundation for potentially preventive
psychosocial interventions and to make a case that the benefits of
preventing psychosis outweigh the risks of treating schizotaxic
adolescents with antipsychotic medication (Tsuang et al, 1999; Cassady et
al, 1998).
CONCLUSION
After about four
decades of introduction of the concept of schizotaxia, it can be seen that
Meehl was right when he predicted that “the endophenotype will eventually
be identified by the biochemical and neurophysiologic aberrations
underlying schizotaxia” (Meehl, 1962). No longer is schizotaxia considered
as a theoretical construct describing the unknown neural substrate of
schizophrenia, but accumulation of research reveals schizotaxia to be a
clinically consequential condition. Looking forward, formulating a
diagnostic criteria for schizotaxia, devising diagnostic methods like
genetic testing, and implementing environmental and pharmacological
interventions are expected to help us in the primary prevention of
schizophrenia in the future.
REFERENCES
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