It has been postulated that to have any liability for schizophrenia, one must inherit a
particular genetic cons...
minority of schizotypal individuals decompensate into clinical schizophrenia. If the
interpersonal regime is favorable a...
evidence supports the view that schizotaxia is a meaningful, clinical condition
(Faraone et al., 2001).
Negative Symptom...
(Toomey et al, 1998). A reexamination of first-degree, nonpsychotic relatives who
were evaluated four years previously r...
Growth hormone response to apomorphine has been reported to differentiate the
relative risk of finding schizophrenia spe...
Firstly, the therapist should have an objective understanding of the patient’s
neuropsychological strengths and weakness...
of ‘at risk’ persons should also be considered. Further research is needed to create a
scientific foundation for potenti...
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Schizotaxia - Dr.Hani


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Schizotaxia - Dr.Hani

  1. 1. 1 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
  2. 2. 2 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
  3. 3. 3 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
  4. 4. 4 (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 funct ioning 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
  5. 5. 5 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).
  6. 6. 6 Firstly, the therapist should have an objective understanding of the patient’s neuropsychological strengths and weaknesses. This knowledge helps patient s 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
  7. 7. 7 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.